CN101151265A - Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent - Google Patents

Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent Download PDF

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CN101151265A
CN101151265A CN 200680009935 CN200680009935A CN101151265A CN 101151265 A CN101151265 A CN 101151265A CN 200680009935 CN200680009935 CN 200680009935 CN 200680009935 A CN200680009935 A CN 200680009935A CN 101151265 A CN101151265 A CN 101151265A
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1h
yl
trifluoromethyl
dihydro
amino
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CN 200680009935
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CN101151265B (en
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李昌锡
邱中星
高基东
金坚太
金庆熙
洪尚勇
金星燮
金玟廷
任贤朝
林东出
金慧珍
韩嬉恩
付松哲
权吴焕
金成澔
许广青
金志迎
廉智浩
吕东俊
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株式会社Lg生命科学
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Priority to KR10-2005-0027756 priority
Priority to KR20050053761 priority
Priority to KR10-2005-0053761 priority
Priority to KR20050085980 priority
Priority to KR10-2005-0085980 priority
Priority to KR10-2005-0122361 priority
Priority to KR20050122361 priority
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Priority to PCT/KR2006/001169 priority patent/WO2006104356A1/en
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems

Abstract

本发明涉及对二肽基肽酶-IV(DPP-IV)显示良好抑制活性的新型化合物,其制备方法,以及含有该化合物作为活性剂的药物组合物。 The present invention relates to dipeptidyl peptidase -IV (DPP-IV) show excellent inhibitory activity of novel compounds, their preparation, and pharmaceutical compositions containing the compounds as an active agent.

Description

二肽基肽酶-Ⅳ抑制化合物,其制备方法,以及含有该化合物作为活性剂的药物组合物 -Ⅳ dipeptidyl peptidase inhibiting compounds, their preparation, and pharmaceutical compositions containing the compounds as an active agent

[0001] 发明领域 [0001] Field of the Invention

[0002] 本发明涉及对二肽基肽酶-IV(DPP-IV)具有良好抑制活性的结构新颖的化合物,其制备方法,以及含有该化合物作为活性剂的药物组合物。 [0002] The present invention relates to a structure having good inhibition activity of novel compounds on dipeptidyl peptidase -IV (DPP-IV), their preparation, and pharmaceutical compositions containing the compounds as an active agent.

[0003] 背景技术 [0003] BACKGROUND OF THE INVENTION

[0004] 糖尿病对人类健康具有严重影响,并伴随多种并发症。 [0004] Diabetes has serious implications for human health, and is accompanied by a variety of complications. 糖尿病主要有两种类型:I型糖尿病,其特征在于由于胰腺细胞的破坏,胰岛素分泌能力很少或没有,以及II型糖尿病,其特征在于其他原因引起的胰岛素缺乏和胰岛素抗性。 There are two main types of diabetes: Type I diabetes, which is characterized in that due to destruction of pancreatic cells, little or no insulin secretory capacity, and type II diabetes, which is characterized by insulin deficiency and other causes of insulin resistance. II型糖尿病分发病率占总体糖尿病患者的90%或以上。 The incidence of Type II diabetes fraction 90% or more overall diabetes. 与糖尿病相伴的并发症的代表性例子包括高脂血症、高血压、视网膜病和肾功能不足(Paul Zimmer et a1,Nature,2001,414,782)。 Representative examples of complications accompanying diabetes include less than hyperlipidemia, hypertension, retinopathy and renal (Paul Zimmer et a1, Nature, 2001,414,782). 磺酰脲类(刺激胰腺细胞分泌胰岛素)、双胍类(抑制肝脏产生葡萄糖)、α-葡糖苷酶抑制剂(抑制葡萄糖在肠中的吸收)等已用作治疗糖尿病的药剂。 Sulfonylureas (stimulating insulin secretion from pancreatic cells), biguanides (inhibiting glucose production by the liver), alpha] -glucosidase inhibitors (inhibiting glucose absorption in the intestines), etc. have been used as an agent for treating diabetes. 近来,过氧化物酶体增殖物激活的受体γ((PPARγ)加速剂(噻唑烷二酮(Thiazolidinediones),增加胰岛素敏感性)作为糖尿病治疗剂已引起了注意。然而,这些药物具有副作用,诸如,低血糖症、增重等(DavidE.Moller,Nature,2001,414,821)。因此,对开发副作用减少、尤其是不会诱导低血糖症和增重的糖尿病治疗剂有强烈的需要。 Recently, peroxisome proliferator-activated receptor γ ((PPARγ) accelerators (thiazolidinedione (Thiazolidinediones), increased insulin sensitivity) as a therapeutic agent for diabetes has attracted attention. However, these drugs have side effects, such as hypoglycemia, weight gain and the like (DavidE.Moller, Nature, 2001,414,821). Thus, reducing the development of side effects, in particular without inducing hypoglycemia and weight gain diabetes therapeutic agents have a strong need.

[0005] 最近,已发现二肽基肽酶-IV(DPP-IV)缺失的小鼠保持着胰高血糖素-样蛋白1(GLP-1)活性和高胰岛素水平,导致血糖水平降低,这提示了其用作糖尿病治疗剂的可能性(Marguet D.et al,Natl.Acad.Sci.USA,(2000)97,6874-6879)。 [0005] Recently, it has been found that dipeptidyl peptidase -IV (DPP-IV) deficient mice maintained glucagon - like protein 1 (GLP-1) activity and high insulin levels, resulting in decreased blood glucose levels, which It suggests the possibility of its use as a therapeutic agent for diabetes (Marguet D.et al, Natl.Acad.Sci.USA, (2000) 97,6874-6879). GLP-1诱导体内胰腺β-细胞的分化和生长,并在胰岛素产生和分泌中发挥重要作用。 GLP-1-induced differentiation and growth of pancreatic β- cells in vivo, and generate and play an important role in secretion of insulin. GLP-1由DPP-IV失活,并已报道DPP-IV抑制剂通过抑制所述失活机制而增加胰岛素分泌。 GLP-1 inactivated by the DPP-IV, and DPP-IV inhibitors have been reported by inhibiting said inactivation mechanism of insulin secretion is increased. DPP-IV抑制剂还正被开发成治疗肥胖,因为其使大鼠有饱足感,并减缓食物在肠道中的消化,导致失重。 DPP-IV inhibitors also are being developed to treat obesity, because it makes sense of satiety in rats and slow down digestion of food in the intestinal tract, leading to weight loss. 此外,许多研究人员也已显示DPP-IV抑制剂在动物实验中控制血糖和脂水平(Pospislik JA,et a1,Diabetes,(2002)51,943-950)。 In addition, many researchers have also shown that DPP-IV inhibitors control blood glucose in animal experiments and lipid levels (Pospislik JA, et a1, Diabetes, (2002) 51,943-950). 就此而论,DPP-IV抑制剂可视为糖尿病治疗的潜在的有用药剂。 In this regard, DPP-IV inhibitors can be considered as potentially useful agents in the treatment of diabetes.

[0006] 迄今为止,开发DPP-IV抑制剂的诸多研究集中于氰基与吡咯烷环键合的材料。 [0006] To date, the development of DPP-IV inhibitors many studies have focused on the material with a cyano group bonded to the pyrrolidine ring. 例如,WO 00/34241公开了由下式所示的DPP-IV抑制剂。 For example, WO 00/34241 discloses DPP-IV inhibitors represented by the following formula.

[0007] [0007]

[0008] 其中R是金刚烷基,且n是0-3。 [0008] wherein R is an adamantyl group, and n is 0-3.

[0009] 其它抑制剂公开在WO 04/064778,WO 03/004498,WO03/082817等中,其中WO 04/064778公开由下式所示的DPP-IV抑制剂。 [0009] Other inhibitors are disclosed in WO 04/064778, WO 03/004498, WO03 / 082817 and the like, wherein the WO 04/064778 discloses DPP-IV inhibitors represented by the following formula.

[0010] [0010]

[0011] 其中Ar是未取代或取代的苯基;R15,R16和R17是氢或烷基;且U、V和W是氮、氧或取代的氮或碳。 [0011] wherein Ar is an unsubstituted or substituted phenyl; R15, R16 and R17 are hydrogen or alkyl; and U, V and W are nitrogen, oxygen, or substituted nitrogen or carbon.

[0012] WO 03/004498公开了由下式所示的DPP-IV抑制剂。 [0012] WO 03/004498 discloses an inhibitor of the formula shown by DPP-IV.

[0013] [0013]

[0014] 其中Ar是未取代或取代的苯基;R18是氢或烷基;以及T是氮或取代的碳。 [0014] wherein Ar is an unsubstituted or substituted phenyl; R18 is hydrogen or alkyl; and T is nitrogen or substituted carbon.

[0015] WO 03/082817公开了由下式所示的DPP-IV抑制剂。 [0015] WO 03/082817 discloses DPP-IV inhibitors represented by the following formula.

[0016] [0016]

[0017] 其中Ar是未取代或取代的苯基;R19,R20和R21是氢或烷基;并且Q是氮或取代的碳。 [0017] wherein Ar is an unsubstituted or substituted phenyl; R19, R20 and R21 is hydrogen or alkyl; and Q is nitrogen or substituted carbon.

[0018] 这些DPP-IV抑制剂在其分子结构中与本发明一样具有酰胺键;然而,如上述这些抑制剂式中Ar所示的未饱和或饱和的苯基完全不同于本发明的饱和或未饱和的5-元或6-元杂环取代基。 [0018] These DPP-IV inhibitors of the present invention as having an amide bond in its molecular structure; however, these inhibitors as described above wherein Ar is a saturated or unsaturated phenyl group shown in the present invention is completely different from the saturated or unsaturated 5-membered or 6-membered heterocyclic substituent. 而且,本发明DPP-IV抑制剂在上述抑制剂的苯基位置具有内酰胺,这尚未公开在现有技术中。 Moreover, DPP-IV inhibitors of the present invention having a lactam at the phenyl position of the inhibitor, which has not been disclosed in the prior art.

[0019] 发明内容 [0019] SUMMARY OF THE INVENTION

[0020] 技术问题 [0020] Technical issues

[0021] 为了开发显示DPP-IV抑制剂效果的化合物,本发明的发明人进行了广泛的研究和众多实验后发现,具有任选取代的内酰胺环结构的化合物针对DPP-IV显示优异的抑制活性。 After [0021] For compounds that are inhibitors of DPP-IV results show the development, the present inventors conducted extensive research and found that a number of experiments, the compound optionally substituted lactam ring structure exhibit excellent inhibition of DPP-IV for the active. 在此发现基础上实现了本发明。 In this finding the present invention achieved on the basis of.

[0022] 因此,本发明目的旨在提供具有任选取代的内酰胺环结构且针对DPP-IV具有良好抑制活性的新颖化合物。 [0022] Accordingly, an object of the present invention is to provide a lactam ring structure optionally having a substituent and a novel compound having excellent activity for inhibiting DPP-IV.

[0023] 本发明的另一个目的旨在提供这类化合物的制备方法。 [0023] Another object of the present invention to provide a method of preparing such compounds.

[0024] 本发明的另一目的旨在提供抑制DPP-IV活性的药物组合物,其包含药物有效量的这些化合物作为活性剂,还提供通过使用本发明化合物用于治疗或预防由DPP-IV的不恰当活性引起的疾病的方法。 [0024] Another object of the present invention is to provide a pharmaceutical composition of inhibiting DPP-IV activity comprising a pharmaceutically effective amount of these compounds as an active agent, also provided by the use of a compound of the invention for the treatment or prevention of a DPP-IV of a disease caused by inappropriate activity.

[0025] 本发明的其他目的和益处对本领域技术人员而言将从下文详细描述中显而易见。 [0025] Other objects and advantages of the present invention are apparent from the following detailed description to those skilled in the art will.

[0026] 技术方案 [0026] Technical Solution

[0027] 根据本发明,提供下式I的化合物。 [0027] According to the present invention, to provide a compound of Formula I.

[0028] [0028]

[0029] 其中 [0029] in which

[0030] (A)A选自下式2-7的取代基: [0030] (A) A formula 2-7 substituents selected from the group:

[0031] [0031]

[0032] 其中R1是氢,或取代或未取代的C1-C4烷基;以及X是碳或氮; [0032] wherein R1 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl; and X is carbon or nitrogen;

[0033] [0033]

[0034] 其中R2是氢,或取代或未取代的C1-C4烷基; [0034] wherein R2 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl;

[0035] [0035]

[0036] 其中R3是氢,或取代或未取代的烷基,环烷基,芳基或杂芳基;以及R'3是氢,CF3; [0036] wherein R3 is hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl; and R'3 is hydrogen, CF3;

[0037] [0037]

[0038] 其中R4是氢,卤素,或取代或未取代的C1-C4烷基,或选自下式6a和6b的取代基: [0038] wherein R4 is hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl, or selected from the following formulas 6a and 6b substituents:

[0039] [0039]

[0040] 其中R5是氢,卤素,或取代或未取代的C1-C4烷基;以及X是氧,硫,或砜; [0040] wherein R5 is hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and X is oxygen, sulfur, or sulfone;

[0041] [0041]

[0042] 其中R6是卤素,或取代或未取代的C1-C4烷基; [0042] wherein R6 is halogen, or a substituted or unsubstituted C1-C4 alkyl;

[0043] (B)B选自下式8-11的取代基: [0043] (B) B is selected from the group substituent of Formula 8-11:

[0044] [0044]

[0045] 其中R7,R8,R9和R10各自独立为氢,卤素,或取代或未取代的C1-C4烷基; [0045] wherein R7, R8, R9 and R10 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl;

[0046] [0046]

[0047] 其中R11,R12和R13各自独立为氢,卤素,或取代或未取代的C1-C4烷基;以及Y是氧,硫或SO2; [0047] wherein R11, R12 and R13 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and Y is oxygen, sulfur or of SO2;

[0048] [0048]

[0049] 其中R14和R15各自独立为氢,卤素,或取代或未取代的C1-C4烷基;以及Z是-CH-或氧,Z为氧时,无R14; [0049] wherein R14 and R15 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and Z is -CH- or oxygen, Z is oxygen, no R14;

[0050] [0050]

[0051] 其中R17是取代或未取代的C1-C4烷基。 [0051] wherein R17 is a substituted or unsubstituted C1-C4 alkyl.

[0052] 其中C1-C4烷基是取代的,如上式所定义,优选以卤素取代的烷基,以及更优选以氟化物取代的烷基。 [0052] wherein C1-C4 alkyl is substituted, as defined in the above formula, the substituent is preferably halogen-substituted alkyl group, and more preferably an alkyl fluoride.

[0053] 在优选实施方案中,式5中的R3选自下列取代基: [0053] In a preferred embodiment, R3 in Formula 5 substituents selected from the following group:

[0054] 氢; [0054] hydrogen;

[0055] 取代或未取代的C1-C4烷基; [0055] a substituted or unsubstituted C1-C4 alkyl;

[0056] 式-CH2-R18,其中R18是C1-C4烷氧基烷基,或未取代或用卤素或羟基取代的C3-C7环烷基,或未取代或用卤素或羟基取代的苯基; [0056] the formula -CH2-R18, wherein R18 is C1-C4 alkoxy group, or an unsubstituted or substituted by halogen or hydroxy a C3-C7 cycloalkyl, or unsubstituted or substituted phenyl with halogen or hydroxy ;

[0057] 取代或未取代的C3-C7环烷基; [0057] a substituted or unsubstituted C3-C7 cycloalkyl group;

[0058] [0058]

[0059] 其中R19和R20各自独立为氢,卤素,或取代或未取代的C1-C4烷基;以及 [0059] wherein R19 and R20 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and

[0060] 未取代或用卤素或羟基取代的5-元或6元杂芳基。 [0060] unsubstituted or substituted with halogen or hydroxy-substituted 5-membered or 6-membered heteroaryl.

[0061] 在上述实施方案中,当C3-C7环烷基和C1-C4烷基是取代的形式时,优选是用卤素或羟基取代的环烷基和烷基。 [0061] In the above embodiments, when C3-C7 cycloalkyl and C1-C4 alkyl is substituted form, preferably with halogen or hydroxy-substituted cycloalkyl and alkyl.

[0062] 如上定义的杂芳基的优选例子包括但不限于2-呋喃,3-呋喃,2-噻吩,3-噻吩,2-吡啶,3-吡啶,4-吡啶,2-吡咯,3-吡咯等。 [0062] Preferred examples of heteroaryl groups as defined above include, but are not limited to, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 3- pyrrole.

[0063] 本发明化合物包括其异构体,而优选的异构体是下式1a的化合物,其中与NH2相邻的碳是手性中心: [0063] The compounds of the present invention include isomers thereof, and the preferred isomer is a compound of formula 1a, wherein the carbon adjacent to NH2 is a chiral center:

[0064] [0064]

[0065] 其中,A和B与式1中的相同。 [0065] wherein the same as in Formula 1 A and B.

[0066] 本发明化合物可与可药用酸形成酸加成物。 Compounds of the invention [0066] may form an acid adduct with a pharmaceutically acceptable acid. 如本发明所用,可药用盐包括无机盐,有机盐,氨基酸盐等,以及更具体而言,无机酸的盐,诸如盐酸,氢溴酸,磷酸或硫酸;有机酸的盐,诸如乙酸,柠檬酸,三氟乙酸,甲酸,马来酸,草酸,琥珀酸,安息香酸,酒石酸,富马酸,扁桃酸,抗坏血酸,苹果酸等;甲磺酸、对-甲苯磺酸等的盐。 As used in the present invention, pharmaceutically acceptable salts include inorganic salts, organic salts, amino acid salts, and more specifically, salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; salts of organic acids, such as acetic acid, citric acid, trifluoroacetic acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, and malic acid; methanesulfonic acid, p - toluenesulfonic acid and the like.

[0067] 本发明化合物或其可药用盐以水合物或溶剂化物的形式存在。 Compound [0067] of the present invention or a pharmaceutically acceptable salt thereof may be present in the form of a hydrate or solvate thereof.

[0068] 在特别优选的实施方案中,本发明式1化合物是如下定义的化合物: [0068] In a particularly preferred embodiment, the present compounds of formula 1 is a compound as defined below:

[0069] 3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-噁唑烷-2-酮; [0069] 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] - oxazolidin-2-one;

[0070] 3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5-甲基-噁唑烷-2-酮; [0070] 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -5-methyl - oxazolidin-2-one;

[0071] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-哌啶-2-酮; [0071] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] - piperidin-2-one;

[0072] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-吡咯烷-2-酮; [0072] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -4-methyl - pyrrolidin-2-one;

[0073] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4,4-二甲基-吡咯烷-2-酮; [0073] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -4,4-dimethyl - pyrrolidin-2-one;

[0074] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氟-吡咯烷-2-酮; [0074] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -3-fluoro - pyrrolidin-2-one;

[0075] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-吡咯烷-2-酮; [0075] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] - pyrrolidin-2-one;

[0076] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氟-哌啶-2-酮; [0076] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -3-fluoro - piperidin-2-one;

[0077] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-甲基-吡咯烷-2-酮; [0077] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -3-methyl - pyrrolidin-2-one;

[0078] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-1,5-二氢-吡咯-2-酮; [0078] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -4-methyl-1,5-dihydro - pyrrolidin-2-one;

[0079] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-哌啶-2-酮; [0079] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -4-methyl - piperidin-2-one;

[0080] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5,5-二氟-哌啶-2-酮; [0080] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -5,5-difluoro - piperidin-2-one;

[0081] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5R-甲基-哌啶-2-酮; [0081] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] 5R-methyl - piperidin-2-one;

[0082] 3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氮杂-双环[3.1.0]己烷-2-酮; [0082] 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -3-aza - bicyclo [3.1.0] hexane-2-one;

[0083] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-三氟甲基-吡咯烷-2-酮; [0083] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -4-trifluoromethyl - pyrrolidin-2-one;

[0084] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-三氟甲基-哌啶-2-酮; [0084] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -4-trifluoromethyl - piperidin-2-one;

[0085] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5-三氟甲基-哌啶-2-酮; [0085] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -5-trifluoromethyl - piperidin-2-one;

[0086] 4-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-6-甲基-吗啉-3-酮; [0086] 4- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a ] pyrazin-7-yl) - butyl] -6-methyl - morpholin-3-one;

[0087] 1-[2S-氨基-4-(3,4-二氢-1H-异喹啉-2-基)-4-氧代-丁基]-哌啶-2-酮; [0087] 1- [2S- Amino-4- (3,4-dihydro -1H- isoquinolin-2-yl) -4-oxo - butyl] - piperidin-2-one;

[0088] 1-[2S-氨基-4-(3,4-二氢-1H-异喹啉-2-基)-4-氧代-丁基]-4-甲基-吡咯烷-2-酮; [0088] 1- [2S- Amino-4- (3,4-dihydro -1H- isoquinolin-2-yl) -4-oxo - butyl] -4-methyl - pyrrolidin-2 ketone;

[0089] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-4,5-二氢-7H-异噁唑并[3,4-c]吡啶-6-基)丁基]-哌啶-2-酮; [0089] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-4,5-dihydro -7H- isoxazolo [3,4-c] pyridin-6-yl ) butyl] - piperidin-2-one;

[0090] 1-[2S-氨基-4-氧代-4-(3-三氟甲基-1,4,5,7-四氢-吡唑并[3,4-c]吡啶-6-基)-]基]-哌啶-2-酮; [0090] 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-4,5,7-tetrahydro - pyrazolo [3,4-c] pyridine-6 yl) -] yl] - piperidin-2-one;

[0091] 1-[2S-氨基-4-氧代-4-(4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-基)-丁基]-5R-甲基-1-哌啶-2-酮; [0091] 1- [2S- amino-4-oxo-4- (4-trifluoromethyl-5,8-dihydro--6H- pyrido [3,4-d] pyrimidin-7-yl) - butyl] -1-5R-methyl-2-one;

[0092] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0092] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0093] (6S)-4-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮; [0093] (6S) -4 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -6-methyl-morpholin-3-one;

[0094] 1-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0094] 1 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0095] 1-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0095] 1 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0096] 1-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0096] 1 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0097] (6S)-4-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0097] (6S) -4 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0098] 1-{(2S)-2-氨基-4-氧代-4-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丁基}-5,5-二氟哌啶-2-酮; [0098] 1 - {(2S) -2- amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] butyl } -5,5-difluoropiperidin-2-one;

[0099] (6S)-4-{(2S)-2-氨基-4-氧代-4-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丁基}-6-甲基吗啉-3-酮; [0099] (6S) -4 - {(2S) -2- amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] butyl} -6-methyl-morpholin-3-one;

[0100] 1-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0100] 1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0101] (6S)-4-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-2-酮; [0101] (6S) -4 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl morpholin-2-one;

[0102] 1-{(2S)-2-氨基-4-[2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0102] 1 - {(2S) -2- amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0103] (6S)-4-{(2S)-2-氨基-4-[2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0103] (6S) -4 - {(2S) -2- amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0104] (5R)-1-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0104] (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0105] 1-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0105] 1 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0106] (6S)-4-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0106] (6S) -4 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0107] (5R)-1-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0107] (5R) -1 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0108] (5R)-1-{(2S)-2-氨基-4-[2-环戊基4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0108] (5R) -1 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0109] (6S)-4-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0109] (6S) -4 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0110] 1-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0110] 1 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0111] (5R)-1-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-5-甲基哌啶-2-酮; [0111] (5R) -1 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1, 3] thiazolo [4,5, c] pyridin -5 (4H) - yl} butyl] -5-methyl-piperidin-2-one;

[0112] (6S)-4-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-6-甲基吗啉-3-酮; [0112] (6S) -4 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1, 3] thiazolo [4,5, c] pyridin -5 (4H) - yl} butyl] -6-methyl-morpholin-3-one;

[0113] 1-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-5,5-二氟哌啶-2-酮; [0113] 1 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl} butyl] -5,5-difluoropiperidin-2-one;

[0114] (5R)-1-{(2S)-2-氨基-4-[2-(4-氟苯基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0114] (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c ] pyridin -5 (4H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0115] (6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(4-氟苯基)6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮; [0115] (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (4-fluorophenyl) 6,7-dihydro [1,3] thiazolo [4 , 5, c] pyridin -5 (4H) - yl] butyl} -6-methyl-morpholin-3-one;

[0116] 1-{(2S)-2-氨基-4-[2-(4-氟苯基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0116] 1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine-5 (4H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0117] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5-甲基哌啶-2-酮; [0117] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7-dihydro [1 , 3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -5-methyl-piperidin-2-one;

[0118] (6S)-4-{(2R)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮; [0118] (6S) -4 - {(2R) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7-dihydro [1 , 3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methyl-morpholin-3-one;

[0119] 1-{(2S)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5,5-二氟哌啶-2-酮; [0119] 1 - {(2S) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7-dihydro [1,3] thiazole and [4,5, c] pyridin -5 (4H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0120] (6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(三氟甲基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮; [0120] (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4 , 5, c] pyridin -5 (4H) - yl] butyl} -6-methyl-morpholin-3-one;

[0121] 1-{(2S)-2-氨基-4-氧代-4-[2-(三氟甲基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5,5-二氟哌啶-2-酮; [0121] 1 - {(2S) -2- amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c ] pyridin -5 (4H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0122] (5R)-1-{(2S)-2-氨基-4-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0122] (5R) -1 - {(2S) -2- amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0123] 1-{(2S)-2-氨基-4-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0123] 1 - {(2S) -2- amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0124] (5R)-1-{(2S)-2-氨基-4-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0124] (5R) -1 - {(2S) -2- amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0125] 1-{(2S)-2-氨基-4-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0125] 1 - {(2S) -2- amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0126] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0126] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0127] 1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0127] 1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0128] (5R)-1-{(2S)-2-氨基-4-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0128] (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0129] 1-{(2S)-2-氨基-4-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0129] 1 - {(2S) -2- amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0130] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0130] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0131] 1-{(2S)-2-氨基-4-氧代-4-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0131] 1 - {(2S) -2- amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0132] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0132] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0133] 1-{(2S)-2-氨基-4-氧代-4-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0133] 1 - {(2S) -2- amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0134] (5R)-1-{(2S)-2-氨基-4-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0134] (5R) -1 - {(2S) -2- amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0135] 1-{(2S)-2-氨基-4-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0135] 1 - {(2S) -2- amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0136] (5R)-1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0136] (5R) -1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0137] 1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0137] 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0138] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0138] (5R) -1 - {(2S) -2- amino-4-oxo -4- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8 - dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0139] 1-{(2S)-2-氨基-4-氧代-4-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0139] 1 - {(2S) -2- amino-4-oxo -4- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0140] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0140] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0141] 1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0141] 1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0142] 1-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0142] 1 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0143] (6S)-4-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0143] (6S) -4 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0144] 1-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0144] 1 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0145] 1-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0145] 1 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0146] (6S)-4-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0146] (6S) -4 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0147] (6R)-4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮; [0147] (6R) -4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazole and [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-morpholin-3-one;

[0148] (6S)-4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮; [0148] (6S) -4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazole and [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-morpholin-3-one;

[0149] (5S)-1-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-5-甲基哌啶-2-酮; [0149] (5S) -1 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazole and [4,3-a] pyrazin -7 (8H) - yl] butyl} -5-methyl-piperidin-2-one;

[0150] (5S)-1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0150] (5S) -1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0151] (5R)-1-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0151] (5R) -1 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0152] (5R)-1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0152] (5R) -1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0153] 1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0153] 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0154] (5R)-4-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0154] (5R) -4 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0155] 1-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0155] 1 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0156] (6S)-4-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0156] (6S) -4 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0157] 1-{(2S)-2-氨基-4-氧代-4-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0157] 1 - {(2S) -2- amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0158] (6S)-4-{(2S)-2-氨基-4-氧代-4-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮; [0158] (6S) -4 - {(2S) -2- amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -6-methyl-morpholin-3-one;

[0159] 1-{(2S)-2-氨基-4-氧代-4-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-5,5-二氟哌啶-2-酮; [0159] 1 - {(2S) -2- amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4, 3-a] pyrazin -7 (8H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0160] (6S)-4-{(2S)-2-氨基-4-氧代-4-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮; [0160] (6S) -4 - {(2S) -2- amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazole and [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-morpholin-3-one;

[0161] 4-{(2S)-2-氨基-4-[2-4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基硫代吗啉-3-酮; [0161] 4 - {(2S) -2- amino-4- [2-4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-thiomorpholine-3-one;

[0162] 1-{(2S)-2-氨基-4-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0162] 1 - {(2S) -2- amino-4- [2-tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0163] (6S)-4-{(2S)-2-氨基-4-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; [0163] (6S) -4 - {(2S) -2- amino-4- [2-tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;

[0164] 4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基硫代吗啉-3-酮; [0164] 4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4, 3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-thiomorpholine-3-one;

[0165] (5R)-1-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0165] (5R) -1 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0166] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0166] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0167] (6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮; [0167] (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -6-methyl-morpholin-3-one;

[0168] 1-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0168] 1 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0169] (5R)-1-{(2S)-2-氨基-4-氧代-4-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; [0169] (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;

[0170] 1-{(2S)-2-氨基-4-氧代-4-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; [0170] 1 - {(2S) -2- amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;

[0171] (5R)-1-{(2S)-2-氨基-4-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0171] (5R) -1 - {(2S) -2- amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0172] 1-{(2S)-2-氨基-4-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; [0172] 1 - {(2S) -2- amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

[0173] 1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基-1,5-二氢-2H-吡咯-2-酮; [0173] 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-1,5-dihydro -2H- pyrrol-2-one;

[0174] 1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基-1,5-二氢-2H-吡咯-2-酮; [0174] 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-1,5-dihydro -2H- pyrrol-2-one;

[0175] 1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基氧代吡咯烷-2-酮; [0175] 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-oxo-2-one;

[0176] 1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基吡咯烷-2-酮; [0176] 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-pyrrolidin-2-one;

[0177] 1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-(三氟甲基)哌啶-2-酮; [0177] 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5- (trifluoromethyl) piperidin-2-one;

[0178] 1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-(三氟甲基)吡咯烷-2-酮; [0178] 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one;

[0179] 1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-(三氟甲基)吡咯烷-2-酮; [0179] 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one;

[0180] 1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基氧代哌啶-2-酮; [0180] 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-oxo-2-one;

[0181] 1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基哌啶-2-酮; [0181] 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-piperidin-2-one;

[0182] (5R)-1-{(2S)-2-氨基-4-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; [0182] (5R) -1 - {(2S) -2- amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;

[0183] 1-{(2S)-2-氨基-4-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮. [0183] 1 - {(2S) -2- amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one.

[0184] 本发明还涉及式1化合物的制备方法。 [0184] The present invention further relates to a method of preparing compounds of Formula 1.

[0185] 作为所述制备的第一种说明性方法,式1化合物可由包括下列步骤的方法制备:将下式12的化合物与式13化合物反应的步骤,以及去除胺保护基P1的步骤: [0185] As a first illustrative method for the preparation of compounds of formula 1 may be prepared by the following steps of the method comprising: the step of compound of formula 12 of the formula 13 reacting, and a step of removing the amine protecting group P1:

[0186] [0186]

[0187] R21NH2G1(13) [0187] R21NH2G1 (13)

[0188] 其中, [0188] wherein,

[0189] R21选自式13a-13d的取代基: [0189] R21 is selected from substituents of formula 13a-13d of the group:

[0190] [0190]

[0191] 其中, [0191] wherein,

[0192] A,B,Y,Z,R7,R8,R9,R10,R11,R12,R13,R14,R15和R17与前述定义的相同; A, B the same as Y, Z, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R17 is as previously defined [0192],;

[0193] R22,R23,R24和R25各自独立为C1-C3烷基; [0193] R22, R23, R24 and R25 are each independently C1-C3 alkyl;

[0194] P1是胺保护基;以及 [0194] P1 is an amine protecting group; and

[0195] G1是无,或盐酸,硫酸或三氟乙酸。 [0195] G1 is nothing, or hydrochloric acid, sulfuric acid or trifluoroacetic acid.

[0196] 上述反应可在有机溶剂,诸如二氯乙烷或环醚(例如,四氢呋喃(THF))存在下于-10至40℃进行。 [0196] The above reaction may be an organic solvent, such as dichloroethane or cyclic ether (e.g., tetrahydrofuran (of THF)) in the presence of -10 to 40 ℃ performed. 反应产物可以通过常规方法,如色谱法,从反应物中分离或纯化。 The reaction product may be, such as chromatography, isolated or purified from the reactants by conventional means.

[0197] 上述式12的化合物可理想地由下列反应流程1制备: [0197] compound of formula 12 may be desirably prepared by the following Reaction Scheme 1:

[0198] [反应流程1] [0198] [Reaction Scheme 1]

[0199] [0199]

[0200] 其中, [0200] wherein,

[0201] a是ClCO2Et,Et3N,THF;NaBH4,MeOH; [0201] a is ClCO2Et, Et3N, THF; NaBH4, MeOH;

[0202] b是TBSCl,咪唑,DMF; [0202] b is TBSCl, imidazole, DMF;

[0203] c是Pd/C,H2(苄基酯)或LiOH-H2O,MeOH-H2O(甲酯或乙酯); [0203] c is Pd / C, H2 (benzyl ester) or LiOH-H2O, MeOH-H2O (methyl or ethyl);

[0204] d是EDC,HOBT,AH; [0204] d is EDC, HOBT, AH;

[0205] e是TBAF,THF; [0205] e is TBAF, THF;

[0206] f是Swern[O]或Dess Martin[O]; [0206] f is Swern [O] or Dess Martin [O];

[0207] A和P1与前述定义相同;以及 [0207] A and P1 are as previously defined; and

[0208] P2是苄基,甲基或乙基。 [0208] P2 is benzyl, methyl or ethyl.

[0209] 更具体而言,将上述式14的羧酸转化成酯酐,然后利用NaBH4在甲醇溶剂存在下还原,生成伯醇。 [0209] More specifically, the carboxylic acid of Formula 14 above is converted into an ester anhydride, and then using NaBH4 reduction in the presence of methanol solvent to produce the primary alcohol. 所得伯醇以叔-丁基二甲基甲硅烷基保护,然后,在苄酯形式的情形下,利用铂络合物和氢进行水解反应,而在甲酯或乙酯形式的情形下,利用氢氧化锂进行水解反应,由此获得羧酸。 The resulting primary alcohol to t - butyl dimethylsilyl group protected, and then, in the case of benzyl ester form, using platinum complex and hydrogen in a hydrolysis reaction, and in the case of methyl or ethyl form, using lithium hydroxide hydrolysis reaction, thereby obtaining a carboxylic acid. 在此,所需的胺基团利用EDC和HOBT,通过偶合反应,可被转化进来,然后去除TBS基团,接着以Swern或Dess-Martin氧化,以获得式12的醛。 Here, the desired amine groups using EDC and HOBT, by a coupling reaction, can be converted in, then TBS group is removed, followed by Swern oxidation or Dess-Martin to obtain an aldehyde of formula 12. 如果胺保护基为Boc,其可利用TFA或HCl去除,如果胺保护基为Cbz,其可利用H2/Pd/C或TMSI去除,以及如果胺保护基为Fmoc,其可利用Et2NH去除。 If the amine protecting group is Boc, it may be removed using TFA or HCl, if the amine protecting group is Cbz, it may utilize H2 / Pd / C or TMSI is removed, and if the amine protecting group is Fmoc, it can be removed using Et2NH.

[0210] 式12中的胺'A'的制备方法阐述于WO 04/064778,WO 03/004498,WO 03/082817等中,或可利用商购的胺。 Amine 12 [0210] wherein 'A' method of preparation are described in WO 04/064778, WO 03/004498, WO 03/082817, etc., or commercially available amines can be used.

[0211] 或者,参考公知方法(例如,J.Med.Chem.1999,42(18),3557-3571;WO 04/069162等),式12化合物可从式14的化合物合成。 [0211] Alternatively, with reference to known methods (e.g., J.Med.Chem.1999,42 (18), 3557-3571; WO 04/069162 etc.), a compound of formula 12 can be synthesized from a compound of formula 14.

[0212] 作为所述制备的第二种说明性方法,式1化合物的制备方法包括下列步骤:将上述式13的化合物与下述式15的化合物反应的步骤,去除酸保护基P3的步骤,以及使所得产物与式AH(其中A与式1中的相同)的化合物反应的步骤,接着去除胺保护基: [0212] As the second illustrative method of preparing the preparation of a compound of Formula 1 comprising the steps of: a step of compound of formula 13 reacting a compound of the following formula 15 with an acid removal step of the protective group P3, and a step of reacting a compound of the formula the resulting product with the AH (wherein a is the same as in formula 1), followed by removing the amine protecting group:

[0213] [0213]

[0214] 其中, [0214] wherein,

[0215] P1与上述定义的相同;和 [0215] P1 the same as defined above; and

[0216] P3为苄基或叔-丁基。 [0216] P3 is benzyl or tert - butyl.

[0217] 例如,上述方法可通过下列反应流程2进行: [0217] For example, the method described above can be carried out by the following reaction scheme 2:

[0218] [反应流程2] [0218] [Reaction Scheme 2]

[0219] [0219]

[0220] 其中, [0220] wherein,

[0221] a)是Na(OAc)3BH,R21NH2G1,和ClCH2CH2Cl; [0221] a) is Na (OAc) 3BH, R21NH2G1, and ClCH2CH2Cl;

[0222] b)是Pd/C,H2(苄基酯)或TFA/CH2Cl2(叔-丁基酯,P1=Boc),然后是Boc2O; [0222] b) is Pd / C, H2 (benzyl ester) or TFA / CH2Cl2 (tert - butyl ester, P1 = Boc), then Boc2O;

[0223] c)是EDC,HOBT,AH; [0223] c) is EDC, HOBT, AH;

[0224] d)是HCl/二噁烷; [0224] d) is HCl / dioxane;

[0225] A和B与前述定义相同; [0225] A and B are the same as defined previously;

[0226] P1是胺保护基,诸如Boc,Cbz或Fmoc; [0226] P1 is an amine protecting group such as Boc, Cbz or Fmoc;

[0227] P2是苄基或叔-丁基; [0227] P2 is benzyl or t - butyl;

[0228] G1为无,或盐酸,硫酸或三氟乙酸。 [0228] G1 is nothing, or hydrochloric acid, sulfuric acid or trifluoroacetic acid.

[0229] 式16化合物的制备方法是公知的(例如,J.Med.Chem.1999,42(18),3557-3571)。 Preparing a compound of [0229] Formula 16 is known (e.g., J.Med.Chem.1999,42 (18), 3557-3571).

[0230] 反应a)在存在诸如二氯乙烷或环醚(例如,四氢呋喃(THF))的有机溶剂下,通过式15的化合物与优选0.7-1.5当量的伯胺(式13化合物)反应,于-10-40℃下进行。 [0230] Reaction a) in (e.g., tetrahydrofuran (THF) under) the presence of an organic solvent such as dichloroethane or cyclic ether, the compound of formula 15 and preferably 0.7 to 1.5 equivalents of primary amine compound (Formula 13) The reaction, carried out at -10-40 ℃. 在此,在与上述相同条件下进一步环化反应,合成式16化合物,并且式16化合物经反应b)转化成式17羧酸。 Here, under the same conditions as described above further cyclization reaction, the synthesis of compounds of formula 16, a compound of formula 16 and reacted b) converted to a carboxylic acid of formula 17.

[0231] 在此,如果保护基P2是苄基,P2在H2/Pd/C条件下去除,合成羧酸。 [0231] Here, if the protecting group P2 is benzyl, P2 at a H2 / Pd / C condition is removed, carboxylic acid. 如果P2是叔-丁基,而P1是Boc时,利用二氯甲烷/TFA一起去除这些保护基,胺基再以Boc保护,合成羧酸。 If P2 is t - butyl, and P1 is Boc, using dichloromethane / TFA removed the protecting group, then to Boc protected amine, carboxylic acid. 利用如此制备的羧酸和胺AH,式18化合物可通过公知反应c)获得。 Using the thus prepared carboxylic acid and amine AH, the compounds of formula 18 can be obtained by a known reaction c).

[0232] 如果胺保护基P1是Boc,式1a化合物通过反应d)获得。 [0232] If the amine protecting group P1 is a compound of Boc, by reaction of Formula 1a d) is obtained. 如果P1是Cbz时,利用H2/Pd/C或TMSI去除P1,如果P1是Fmoc,利用Et2NH去除P1,从而获得式1a化合物。 If P1 is Cbz, using H2 / Pd / C or TMSI remove P1, if P1 is Fmoc, it is removed using Et2NH P1, to obtain a compound of formula 1a.

[0233] 反应c)中的胺AH可以通过在WO 04/064778,WO 04/007468等中阐述的方法制备,或利用可商购的胺。 Amine AH [0233] The reaction c) may be by WO 04/064778, WO 04/007468, etc. The method of preparation set forth, or using commercially available amines.

[0234] 在反应c)的胺中,如下定义的胺例如可通过下列反应流程3合成: [0234] In the amine c), the amine as defined below, for example, may be synthesized by the following reaction scheme 3:

[0235] [反应流程3] [0235] [Reaction Scheme 3]

[0236] [0236]

[0237] 其中, [0237] wherein,

[0238] a是LHMDS,CF3CO2Et,DME; [0238] a is LHMDS, CF3CO2Et, DME;

[0239] b是(1)R21C=NH(NH2),EtOH或iPrOH,回流, [0239] b is (1) R21C = NH (NH2), EtOH or iPrOH, reflux,

[0240] (2)R21C=NH(NH2)·HCl,NaOEt,EtOH或iPrOH,回流, [0240] (2) R21C = NH (NH2) · HCl, NaOEt, EtOH or iPrOH, reflux,

[0241] (3)R21C=NH(NH2),cat.BF3·OEt2,iPrOH,回流,或 [0241] (3) R21C = NH (NH2), cat.BF3 · OEt2, iPrOH, reflux, or

[0242] (4)R21C=NH(NH2),吡啶,回流; [0242] (4) R21C = NH (NH2), pyridine, reflux;

[0243] c是HCl/二噁烷或HCl/乙酸乙酯; [0243] c is HCl / dioxane or HCl / ethyl acetate;

[0244] R21是氢,烷基或芳基。 [0244] R21 is hydrogen, alkyl or aryl.

[0245] 更具体而言,式20化合物可通过利用LHMDS从式19化合物制成烯醇化物,然后向其中加入三氟乙酸而制备(参见:J.Fluorine Chem.2003,123(2),267-272)。 [0245] More specifically, the compound of formula 20 can be obtained by using a compound of formula 19 is made from LHMDS enolate, is then prepared (see Thereto was added trifluoroacetic acid: J.Fluorine Chem.2003,123 (2), 267 -272). 存在多种从式20化合物制备具有嘧啶环的化合物21的方法,其中优选利用BF3·OEt2作为催化剂的方法(Synthesis 2000,12,1738-1748)和利用吡啶作为溶剂的方法(Tetrahedron 1983,39(19),3197-3199),以得到好的收率。 There are a variety of formula 20 from the compound having a pyrimidine ring preparation method 21, wherein the method preferably using BF3 · OEt2 method as a catalyst (Synthesis 2000,12,1738-1748) and using pyridine as a solvent (Tetrahedron 1983,39 ( 19), 3197-3199), to afford good yields. 利用如此制备的式21化合物,可获得所需的式22化合物。 Using the compound of Formula 21 thus prepared, the compound of formula 22 obtained desired.

[0246] 作为所述制备的第三种说明性方法,式1化合物可通过包括上述式15的化合物与下述式23的化合物反应步骤的方法制备: [0246] As the third illustrative method of preparing compounds of formula 1 may be prepared comprising a compound of formula 15 with a compound of Formula 23 by the following reaction step by:

[0247] [0247]

[0248] 其中, [0248] wherein,

[0249] G2是无或酸,优选盐酸,硫酸或三氟乙酸; [0249] G2 is absent or an acid, preferably hydrochloric acid, sulfuric acid or trifluoroacetic acid;

[0250] R26是氢,取代或未取代的C1-C4烷基。 [0250] R26 is hydrogen, a substituted or unsubstituted C1-C4 alkyl.

[0251] 如果式15化合物与式23化合物反应,在该化合物发生环化反应,其制备方式与第二种说明性方法中的式13化合物相同,利用COCl2形成B部分,以及随后反应以与第二种说明性方法中的相同方式进行,合成式1化合物。 [0251] If the compound of formula 15 with a compound of formula 23, the compound undergoes a cyclization reaction, a compound prepared in the same manner as in the second illustrative method Formula 13, Part B using COCl2 formed, and subsequently in the reaction with the first the same manner as two kinds of illustrative methods, the synthesis of compounds of formula 1. 从式15化合物和式12化合物的该反应,可制备式1化合物,其中式10中的Z是O。 From the reaction of compounds of formula 15 and a compound of the formula 12 compound of Formula 1 may be prepared, wherein in the formula 10 Z is O.

[0252] 作为起始材料的化合物是已知化合物,除了其制备方法特别描述于本发明的情形之外,或者它们可以通过已知方法或与之相似的方法,从已知化合物合成。 [0252] The compound starting material are known compounds, except the case particularly their preparation are described in the present invention, or they may be by known methods or methods similar thereto, synthesized from known compounds.

[0253] 通过常规方法,诸如重结晶,离子电泳,硅胶柱层析,离子交换树脂色谱等,式1化合物可从反应产物中分离和纯化。 [0253] by a conventional method, such as recrystallization, ion electrophoresis, silica gel column chromatography, ion exchange resin chromatography, etc., the compound of Formula 1 can be isolated and purified from the reaction product.

[0254] 如上所述,本发明化合物、其制备的起始材料和中间体可通过多种方法合成,也应解释成包括在本发明与制备式1化合物有关的范围之内。 [0254] As described above, the compounds of the present invention, their preparation starting materials and intermediates can be synthesized by various methods, it should be interpreted to be included within the scope of the present invention is related to the preparation of compounds of formula 1.

[0255] 同样,本发明提供用于抑制DPP-IV的药物组合物,所述组合物包括式1化合物或其可药用盐以及可药用载体。 [0255] Also, the present invention provides a pharmaceutical composition for the inhibition of DPP-IV, the composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0256] 式1化合物根据所需用途可以多种药物剂型给药。 Compound [0256] Formula 1 more pharmaceutical dosage form according to the desired use can. 在制备本发明药物组合物中,活性剂,更具体而言是式1化合物,可与一种或多种可药用载体混合,所述载体的选择取决于待制备的剂型。 In the pharmaceutical compositions of the present invention, the active agent, more specifically a compound of formula 1, it can be mixed with one or more pharmaceutically acceptable carriers, selecting the carrier will depend on the dosage form to be prepared. 例如,本发明药物组合物可配制成适合注射或口服的剂型。 For example, the pharmaceutical compositions of the invention may be formulated into dosage forms suitable for injection or oral administration.

[0257] 式1化合物可以常规方式利用已知可药用载体和赋形剂配制,并呈现为单位剂量形式或多剂量容器。 Compound [0257] Formula 1 may in a conventional manner using known pharmaceutically acceptable carriers and excipients and presented in unit dosage form or multi-dose containers. 制剂可采用诸如油性或水性媒介的溶液、悬浮液或乳液的形式,并可含有常规分散剂,悬浮剂或稳定剂。 The formulation may take the form of suspensions or emulsions in oily or aqueous media, such as a solution, and may contain conventional dispersing, suspending or stabilizing agents. 或者,活性剂可采用粉末形式,用前以消毒的无热原水复溶。 Alternatively, the active agent can be in powder form before use in a non-heat disinfection of raw water reconstitution. 式1化合物还可配制成含有常规栓剂基质例如可可脂或者甘油酯的栓剂。 The compounds of formula 1 may also be formulated as suppositories containing conventional suppository bases such as cocoa butter or glycerides. 口服固体剂型包括胶囊,片剂,丸药,粉末和颗粒。 Oral solid dosage forms include capsules, tablets, pills, powders and granules. 优选剂型是胶囊和片剂。 Preferred dosage forms are capsules and tablets. 片剂和丸药优选被包被。 Tablets and boluses are preferably coated. 将式1化合物作为活性剂,混合无活性的稀释剂如蔗糖、乳糖、淀粉等,以及载体如润滑剂,例如,硬脂酸镁,包括崩解剂、粘合剂等,可获得口服固体剂型。 The compound of formula 1 as the active agent, mixing an inactive diluent such as sucrose, lactose, starch and the like, and a carrier such as lubricants, e.g., magnesium stearate, including disintegrator, binder and the like, oral solid dosage forms obtained .

[0258] 如果需要,本发明的式1化合物及含有该化合物的组合物可与其他药剂组合给药,例如其他糖尿病治疗剂。 [0258] If desired, the compounds of formula 1 according to the present invention and compositions containing the compound may be administered in combination with other agents, for example, other diabetes treating agents.

[0259] 当制剂呈现为单位剂型时,式1化合物作为活性剂的含量优选为约0.1~1,500mg单位剂量。 [0259] When the formulation is presented in unit dosage form, the compound of Formula 1 as an active agent content is preferably about 0.1 ~ 1,500mg unit dose. 式1化合物的剂量取决于对象的体重和年龄,病患的性质和严重程度,以及处方医师的判断。 The nature and severity of the weight and age of the patient dose of the compound of Formula 1 depends on the subject, and the judgment of the prescribing physician. 对成人给药而言,根据剂量的频率和浓度,所需的剂量范围约1-500mg/天。 For adult administration, the dosage according to the frequency and concentration, the desired dosage range from about 1-500 mg / day. 对成人肌内或静脉内给药而言,总剂量约5~300mg/天是足够的。 For intramuscular or intravenous administration for adults, a total dosage of about 5 ~ 300mg / day is sufficient. 在有些患者中,日剂量会比这高。 In some patients, the daily dose will be higher than this.

[0260] 此外,本发明提供了权利要求1限定的式1化合物在制备用于治疗或预防涉及DPP-IV不当活性的疾病的药物中的应用。 [0260] Further, the present invention provides a compound of formula manufacture of a medicament for the treatment or prevention of diseases involving inappropriate activity of DPP-IV in the compound of claim 1.

[0261] DPP-IV不当水平引起的疾病的代表性例子包括,但不限于,糖尿病,肥胖等上述疾病。 [0261] Representative examples of inappropriate levels of DPP-IV induced diseases include, but are not limited to, diabetes, obesity and other diseases described above. 在糖尿病中,本发明优选治疗和预防II型糖尿病。 In diabetes, the present invention is preferably for the treatment and prevention of type II diabetes.

[0262] 发明的实施方式 [0262] Embodiment of the Invention

[0263] 本发明现在通过下列制备和实施例更详细加以说明。 [0263] The present invention will now be described more in detail by the following Preparations and Examples. 然而,应理解的是,本发明不限于这些具体的制备和实施例,并且可以进行可被本发明所属领域技术人员所能认识的到多种修改。 However, it should be appreciated that the present invention is not limited to these specific preparations and examples, and may be carried out may be recognized by the skilled in the art that various modifications of the present invention.

[0264] 制备1:合成3-氨基甲基-4,4,4-三氟-丁酸乙酯盐酸盐 [0264] Preparation 1: Synthesis of 3-aminomethyl-4,4,4-trifluoro - butyric acid ethyl ester hydrochloride

[0265] (1)合成4,4,4-三氟-3-硝基甲基-丁酸乙酯 [0265] (1) Synthesis of 4,4,4-trifluoro-methyl-3-nitro - butyric acid ethyl ester

[0266] 混合1.0g(5.94mmol)4,4,4-三氟-2-丁烯酸乙酯、0.15mL(1.19mmol)1,1,3,3-四甲基胍和1.6mL(29.8mmol)硝基甲烷。 [0266] mixing 1.0g (5.94mmol) 4,4,4- trifluoro-2-butenoate, 0.15mL (1.19mmol) 1,1,3,3- tetramethylguanidine and 1.6mL (29.8 mmol) nitromethane. 所得混合物冷却至0℃,然后室温下搅拌3小时,接着加入100mL乙酰乙酸乙酯。 The resulting mixture was cooled to 0 deg.] C, then stirred at room temperature for 3 hours, followed by addition of 100mL of ethyl acetoacetate. 反应混合物用水洗涤,然后有机层用无水硫酸镁干燥。 The reaction mixture was washed with water, then the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,得到1.1g(4.80mmol)标题化合物,收率81%。 The solvent was distilled off under reduced pressure, to give 1.1g (4.80mmol) of the title compound in a yield of 81%.

[0267] NMR:1H-NMR(CDCl3)δ5.21~4.59(2H,m),4.22(2H,q,J=8Hz),3.67~3.64(1H,m),2.82~2.72(1H,m),2.63~2.57(1H,m),1.28(3H,t,J=8Hz) [0267] NMR: 1H-NMR (CDCl3) δ5.21 ~ 4.59 (2H, m), 4.22 (2H, q, J = 8Hz), 3.67 ~ 3.64 (1H, m), 2.82 ~ 2.72 (1H, m) , 2.63 ~ 2.57 (1H, m), 1.28 (3H, t, J = 8Hz)

[0268] 质量(EI)176(M++1) [0268] mass (EI) 176 (M ++ 1)

[0269] (2)合成N-羟基-3-(叔-丁氧基羰基氨基-甲基)-4,4,4-三氟-丁酸乙酯 [0269] (2) Synthesis of N- hydroxy-3- (tert - butoxycarbonylamino-methyl) - 4,4,4-trifluoro - butyric acid ethyl ester

[0270] 将上述步骤(1)得到的1.1g(4.80mmol)4,4,4-三氟-3-硝基甲基-丁酸乙酯溶解于20mL甲醇,然后向其中加入1.85g(.8.47mmo[)二碳酸二-叔-丁酯。 [0270] The above step (1) obtained 1.1g (4.80mmol) 4,4,4- trifluoro-3-nitro-methyl - butyric acid ethyl ester was dissolved in 20mL of methanol, and thereto was added 1.85g (. 8.47mmo [) di - t - butyl ester. 反应利用180mg 10%钯/碳,在大气压下进行15小时。 The reaction using 180mg 10% palladium / carbon under atmospheric pressure for 15 hours. 反应液经Cellite过滤,减压下蒸馏,无需进一步纯化,得到1.5g(4.80mmol)标题化合物,收率100%。 The Cellite The reaction solution was filtered, evaporated under reduced pressure, without further purification, to give 1.5g (4.80mmol) of the title compound, yield 100%.

[0271] NMR:1H-NMR(CDCl3)δ6.48(1H,s),4.20(2H,q,J=8Hz),3.89~3.83(1H,m),3.66~3.62(1H,m),3.24~3.17(1H,m),2.76~2.68(1H,m),2.53(1H,dd,J=8Hz,16Hz),1.48(9H,s),1.25(3H,t,J=8Hz) [0271] NMR: 1H-NMR (CDCl3) δ6.48 (1H, s), 4.20 (2H, q, J = 8Hz), 3.89 ~ 3.83 (1H, m), 3.66 ~ 3.62 (1H, m), 3.24 ~ 3.17 (1H, m), 2.76 ~ 2.68 (1H, m), 2.53 (1H, dd, J = 8Hz, 16Hz), 1.48 (9H, s), 1.25 (3H, t, J = 8Hz)

[0272] 质量(EI)262(M++1) [0272] mass (EI) 262 (M ++ 1)

[0273] (3)合成3-(叔-丁氧基羰基氨基-甲基)-4,4,4-三氟-丁酸乙酯 [0273] (3) Synthesis of 3- (tert - butoxycarbonylamino-methyl) - 4,4,4-trifluoro - butyric acid ethyl ester

[0274] 将上述步骤(2)得到的760mg(2.41mmol)N-羟基-3-(叔-丁氧基羰基氨基-甲基)-4,4,4-三氟-丁酸乙酯溶解于80mL甲醇和40mL水,然后向其中加入2.4g(28.9mmol)乙酸钠,接着室温下滴加4mL(4.81mmol)20%三氯化钛水溶液。 [0274] The above step (2) to give the 760mg (2.41mmol) N- hydroxy-3- (tert - butoxycarbonylamino-methyl) - 4,4,4-trifluoro - butyric acid ethyl ester was dissolved in 80mL methanol and 40mL of water, then added 2.4g (28.9mmol) of sodium acetate, followed by dropwise addition of 4mL (4.81mmol) 20% titanium trichloride solution at room temperature. 20分钟之后,向溶液中加入300mL乙酰乙酸乙酯,反应液用水洗涤,而有机层用无水硫酸镁干燥。 After 20 min, to the solution was added 300mL ethyl acetoacetate, the reaction solution was washed with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后残留物通过柱层析纯化,得到550mg(2.24mmol)标题化合物,收率92%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 550mg (2.24mmol) of the title compound in 92% yield.

[0275] NMR:1H-NMR(CDCl3)δ4.70(1H,s),4.18(2H,q,J=6.8Hz),3.64~3.53(1H,m),3.35~3.34(1H,m),3.05~2.90(1H,m),2.60(1H,dd,J=5.2Hz,16.4Hz),2.48(1H,dd,J=8Hz,16.4Hz),1.43(9H,s),1.27(3H,t,J=6.8Hz) [0275] NMR: 1H-NMR (CDCl3) δ4.70 (1H, s), 4.18 (2H, q, J = 6.8Hz), 3.64 ~ 3.53 (1H, m), 3.35 ~ 3.34 (1H, m), 3.05 ~ 2.90 (1H, m), 2.60 (1H, dd, J = 5.2Hz, 16.4Hz), 2.48 (1H, dd, J = 8Hz, 16.4Hz), 1.43 (9H, s), 1.27 (3H, t , J = 6.8Hz)

[0276] 质量(EI)246(M++1) [0276] mass (EI) 246 (M ++ 1)

[0277] (4)合成3-氨基甲基-4,4,4-三氟-丁酸乙酯盐酸盐 [0277] (4) Synthesis of 3-aminomethyl-4,4,4-trifluoro - butyric acid ethyl ester hydrochloride

[0278] 将上述步骤(3)获得的170mg(0.69mmol)3-(叔-丁氧基羰基氨基-甲基)-4,4,4-三氟-丁酸乙酯溶解于6mL以盐酸气体饱和的乙酸乙酯,接着室温下搅拌3小时。 [0278] The above step (3) 170mg obtained in (0.69mmol) 3- (tert - butoxycarbonylamino-methyl) - 4,4,4-trifluoro - butyric acid ethyl ester was dissolved in hydrochloric acid gas 6mL saturated ethyl acetate, followed by stirring at room temperature for 3 hours. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到110mg(0.69mmol)标题化合物,收率86%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 110mg (0.69mmol) of the title compound in 86% yield.

[0279] NMR:1H-NMR(CDCl3)δ8.50(2H,brs),4.18(2H,q,J=4Hz),3.50~3.20(3H,m),2.97~2.64(2H,m),1.24(3H,t,J=4Hz) [0279] NMR: 1H-NMR (CDCl3) δ8.50 (2H, brs), 4.18 (2H, q, J = 4Hz), 3.50 ~ 3.20 (3H, m), 2.97 ~ 2.64 (2H, m), 1.24 (3H, t, J = 4Hz)

[0280] 质量(EI)182(M++1) [0280] mass (EI) 182 (M ++ 1)

[0281] 制备2:合成4-氨基-3-甲基-丁酸甲酯盐酸盐 [0281] Preparation 2: Synthesis of 4-amino-3-methyl - butyric acid methyl ester hydrochloride

[0282] (1)合成3-甲基-4-硝基-丁酸甲酯 [0282] (1) Synthesis of 3-methyl-4-nitro - butyrate

[0283] 混合3g(29.9mmol)反-2-丁烯酸甲酯、0.69g(5.99mmol)四甲基胍和9.14g(149mmol)硝基甲烷。 [0283] mixed 3g (29.9mmol) of methyl 2-butene, 0.69g (5.99mmol) tetramethylguanidine and 9.14g (149mmol) nitromethane. 所得混合物室温下搅拌24天。 The resulting mixture was stirred at room temperature for 24 days. 向溶液加入100mL乙酰乙酸乙酯,反应液用水洗涤,然后有机层用无水硫酸镁干燥。 Washed with 100mL ethyl acetoacetate, the reaction solution was added to the solution washed with water, then the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后残留物通过柱层析纯化,得到5.7g(23.6mmol)标题化合物,收率100%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 5.7g (23.6mmol) of the title compound, 100% yield.

[0284] NMR:1H-NMR(CDCl3)δ4.48(1H,dd,J=4Hz,12Hz),4.35(1H,dd,J=4Hz,12Hz),3.71(3H,s),2.84~2.74(1H,m),2.47(1H,dd,J=4Hz,16Hz),2.37(1H,dd,J=8Hz,16Hz),1.11(3H,d,J=8Hz) [0284] NMR: 1H-NMR (CDCl3) δ4.48 (1H, dd, J = 4Hz, 12Hz), 4.35 (1H, dd, J = 4Hz, 12Hz), 3.71 (3H, s), 2.84 ~ 2.74 ( 1H, m), 2.47 (1H, dd, J = 4Hz, 16Hz), 2.37 (1H, dd, J = 8Hz, 16Hz), 1.11 (3H, d, J = 8Hz)

[0285] 质量(EI)162(M++1) [0285] mass (EI) 162 (M ++ 1)

[0286] (2)合成N-叔-丁氢基羰基羟基-4-叔-丁氧基羰基氨基-33-二甲基-丁酸甲酯 [0286] (2) Synthesis of N- t - butyl hydrogen-ylcarbonyl-hydroxy-4-tert - butoxycarbonylamino-dimethyl amino -33- - butyric acid methyl ester

[0287] 将上述步骤(1)获得的4g(24.8mmol)3-甲基-4-硝基-丁酸甲酯溶解于50mL甲醇,然后向其中加入10.4g(47.6mmol)二碳酸二-叔-丁酯。 4g [0287] The above step (1) obtained in (24.8mmol) 3- methyl-4-nitro - butyric acid methyl ester was dissolved in 50mL of methanol, then added 10.4g (47.6mmol) di - t - butyl. 反应用500mg 10%的钯/碳,在50psi压力下进行9小时。 The reaction with 500mg 10% palladium / carbon at 50psi pressure for 9 hours. 反应液用Cellite过滤,减压下馏出,然后通过柱层析纯化残留物,得到3.6g(10.3mmol)标题化合物和1.1g(4.45mmol)N-羟基-4-叔-丁氧基羰基氨基-3,3-二甲基-丁酸甲酯,收率62%。 The reaction solution was filtered by Cellite, distilled off under reduced pressure, and the residue was purified by column chromatography to give 3.6g (10.3mmol) of the title compound 1.1g (4.45mmol) N- hydroxy-4-t - butoxycarbonyl group 3,3-dimethyl - butyric acid methyl ester, 62% yield.

[0288] 质量(EI)348(M++1) [0288] mass (EI) 348 (M ++ 1)

[0289] (3)合成N-羟基-4-叔-丁氧基羰基氨基-33-二甲基-丁酸甲酯 [0289] (3) Synthesis of N- hydroxy-4-tert - butoxycarbonylamino-dimethyl amino -33- - butyric acid methyl ester

[0290] 将上述步骤(2)获得的600mg(1.72mmol)N-叔-丁氧基羰基羟基-4-叔-丁氧基羰基氨基-3,3-二甲基-丁酸甲酯溶解于80mL甲醇,接着加入碳酸氢钠250,并在80℃搅拌9小时。 [0290] The above step (2) 600mg obtained in (1.72mmol) N- tert - butoxycarbonyl-hydroxy-4-tert - butoxycarbonylamino-3,3-dimethyl - butyric acid methyl ester was dissolved in 80mL of methanol, followed by addition of sodium bicarbonate 250 and stirring at 80 ℃ 9 hours. 向溶液中加入200ml乙酸乙酯,反应液用水洗涤,而有机层用无水硫酸镁干燥。 Washed with 200ml of ethyl acetate, water was added to the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后残留物通过柱层析纯化,得到332mg(1.34mmol)标题化合物,收率77%。 The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 332mg (1.34mmol) of the title compound in 77% yield.

[0291] NMR:1H-NMR(CDCl3)δ7.27(1H,brs),3.49(3H,s),3.46(1H,dd,J=4Hz,12Hz),3.33(1H,dd,J=5.6Hz,14.4Hz),2.51~2.42(1H,m),2.39(1H,dd,J=4Hz,16Hz),2.22(1H,dd,J=4Hz,16Hz),1.48(9H,s),0.98(3H,d,J=8Hz) [0291] NMR: 1H-NMR (CDCl3) δ7.27 (1H, brs), 3.49 (3H, s), 3.46 (1H, dd, J = 4Hz, 12Hz), 3.33 (1H, dd, J = 5.6Hz , 14.4Hz), 2.51 ~ 2.42 (1H, m), 2.39 (1H, dd, J = 4Hz, 16Hz), 2.22 (1H, dd, J = 4Hz, 16Hz), 1.48 (9H, s), 0.98 (3H , d, J = 8Hz)

[0292] 质量(EI)248(M++1) [0292] mass (EI) 248 (M ++ 1)

[0293] (4)合成4-叔-丁氧基羰基氨基-3-甲基-丁酸甲酯 [0293] (4) Synthesis of 4-tert - butoxycarbonylamino-3-methyl - butyric acid methyl ester

[0294] 除了利用上述步骤(3)获得的330mg(1.33mmol)N-羟基-4-叔-丁氧基羰基氨基-3,3-二甲基-丁酸甲酯之外,以制备1(3)相同的方式,获得213mg(0.92mmol)标题化合物,收率47%。 [0294] 330mg (1.33mmol) except for using the above-described step (3) to obtain the N- hydroxy-4- tert - butoxycarbonylamino-3,3-dimethyl - butyric acid methyl ester addition to Preparation 1 ( 3) in the same manner to obtain 213mg (0.92mmol) of the title compound in 47% yield.

[0295] NMR:1H-NMR(CDCl3)δ4.65(1H,brs),3.68(3H,s),3.10~3.00(2H,m),2.38~2.33(1H,m),2.20~2.05(2H,m),1.44(9H,s),0.96(3H,d,J=8Hz) [0295] NMR: 1H-NMR (CDCl3) δ4.65 (1H, brs), 3.68 (3H, s), 3.10 ~ 3.00 (2H, m), 2.38 ~ 2.33 (1H, m), 2.20 ~ 2.05 (2H , m), 1.44 (9H, s), 0.96 (3H, d, J = 8Hz)

[0296] 质量(EI)232(M++1) [0296] mass (EI) 232 (M ++ 1)

[0297] (5)合成4-氨基-3-甲基-丁酸甲酯盐酸盐 [0297] (5) Synthesis of 4-amino-3-methyl - butyric acid methyl ester hydrochloride

[0298] 除了利用上述步骤(4)获得的100mg(0.43mmol)4-叔-丁氧基羰基氨基-3-甲基-丁酸甲酯之外,以制备1(4)相同的方式,获得62mg(0.36mmol)标题化合物,收率83%。 [0298] 100mg except for using the above-described step (4) obtained in (0.43mmol) 4- tert - butoxycarbonylamino-3-methyl - butyrate addition, 1 (4) was prepared in the same manner to obtain 62mg (0.36mmol) of the title compound in 83% yield.

[0299] NMR:1H-NMR(CDCl3)δ8.26(2H,brs),3.68(3H,s),3.10~2.9(2H,m),2.77~2.35(3H,m),1.13(3H,d,J=8Hz) [0299] NMR: 1H-NMR (CDCl3) δ8.26 (2H, brs), 3.68 (3H, s), 3.10 ~ 2.9 (2H, m), 2.77 ~ 2.35 (3H, m), 1.13 (3H, d , J = 8Hz)

[0300] 质量(EI)168(M++1) [0300] mass (EI) 168 (M ++ 1)

[0301] 制备3:合成4-氨基-2-氟-丁酸甲酯盐酸盐 [0301] Preparation 3: Synthesis of 4-Amino-2-fluoro - butyric acid methyl ester hydrochloride

[0302] (1)合成2-氧代-吡咯烷-1-羧酸叔-丁酯 [0302] (1) Synthesis of 2-oxo - pyrrolidine-1-carboxylic acid tert - butyl ester

[0303] 将1g(11.7mmol)2-吡咯烷酮溶解于15mL二氯甲烷,然后向其中加入2.5mL(17.8mmol)三乙胺、107mg(0.87mmol)二甲基氨基吡啶和2.7g(12.3mmol)二碳酸二-叔-丁酯。 [0303] A 1g (11.7mmol) 2- pyrrolidone was dissolved in 15mL of dichloromethane, to which was then added 2.5mL (17.8mmol) of triethylamine, 107mg (0.87mmol) of dimethylaminopyridine and 2.7 g (12.3 mmol) di - t - butyl ester. 反应液室温下搅拌8小时。 The reaction solution was stirred at room temperature for 8 hours. 向溶液加入100mL乙酸乙酯,反应液用水洗涤,然后有机层用无水硫酸镁干燥。 Washed with 100mL ethyl acetate, water was added to the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后残留物通过柱层析纯化,得到1.2g(6.47mmol)标题化合物,收率55%。 The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 1.2g (6.47mmol) of the title compound in 55% yield.

[0304] NMR:1H-NMR(CDCl3)δ3.76~3.73(2H,m),2.53~2.49(2H,m),2.04~1.88(2H,m),1.53(9H,s) [0304] NMR: 1H-NMR (CDCl3) δ3.76 ~ 3.73 (2H, m), 2.53 ~ 2.49 (2H, m), 2.04 ~ 1.88 (2H, m), 1.53 (9H, s)

[0305] 质量(EI)186(M++1) [0305] mass (EI) 186 (M ++ 1)

[0306] (2)合成3-氟-2-氧代-吡咯烷-1-羧酸叔-丁酯 [0306] (2) Synthesis of 3-fluoro-2-oxo - pyrrolidine-1-carboxylic acid tert - butyl ester

[0307] 将上述步骤(1)获得的300mg(1.61mmol)2-氧代-吡咯烷-1-羧酸叔-丁酯溶解于四氢呋喃,并冷却至-78℃。 300mg [0307] The above step (1) obtained in (1.61mmol) 2- oxo - pyrrolidine-1-carboxylic acid tert - butyl ester was dissolved in tetrahydrofuran and cooled to -78 ℃. 向所得溶液滴加1.7mL(1.7mmol)1.0M双(三甲基甲硅烷基)氨化锂的四氢呋喃溶液,接着搅拌1小时。 Solution of lithium amide in tetrahydrofuran, followed by stirring the resultant solution was added dropwise 1.7mL (1.7mmol) 1.0M bis (trimethyl silyl) for 1 hour. 向所得溶液加入561mg(1.78mmol)N-氟代苯磺酰亚胺,然后温度逐渐升高至-30℃,2小时。 To the resulting solution was added 561mg (1.78mmol) N- fluorobenzene sulfonimide, and then the temperature was gradually raised to -30 ℃, 2 hours. 向溶液加入100mL乙酰乙酸乙酯,反应液以氯化铵水溶液洗涤,然后有机层用无水硫酸镁干燥。 100mL ethyl acetoacetate was added to the solution, the reaction was washed with aqueous ammonium chloride, and the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到60mg(0.29mmol)标题化合物,收率18%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 60mg (0.29mmol) of the title compound in a yield of 18%.

[0308] NMR:1H-NMR(CDCl3)δ5.16~5.12(0.5H,m),5.01~4.94(0.5H,m),3.91~3.85(1H,m),3.64~3.57(1H,m),2.50~2.45(1H,m),2.25~2.13(1H,m),1.54(9H,s) [0308] NMR: 1H-NMR (CDCl3) δ5.16 ~ 5.12 (0.5H, m), 5.01 ~ 4.94 (0.5H, m), 3.91 ~ 3.85 (1H, m), 3.64 ~ 3.57 (1H, m) , 2.50 ~ 2.45 (1H, m), 2.25 ~ 2.13 (1H, m), 1.54 (9H, s)

[0309] 质量(EI)204(M++1) [0309] mass (EI) 204 (M ++ 1)

[0310] (3)合成4-叔-丁氧基羰基氨基-2-氟-丁酸甲酯 [0310] (3) Synthesis of 4-tert - butoxycarbonylamino-2-fluoro - butyric acid methyl ester

[0311] 将上述步骤(2)获得的60mg(0.29mmol)3-氟-2-氧代-吡咯烷-1-羧酸叔-丁酯溶解于3mL甲醇,然后0℃下向其中加入32mg(0.59mmol)甲醇钠。 [0311] The above step (2) obtained 60mg (0.29mmol) 3- fluoro-2-oxo - pyrrolidine-1-carboxylic acid tert - butyl ester was dissolved in 3mL of methanol, and then was added thereto at 0 ℃ 32 mg of ( 0.59 mmol) of sodium methoxide. 1小时之后,向溶液加入10mL乙酸乙酯,反应液用氯化铵水溶液洗涤,有机层用无水硫酸镁干燥。 After 1 h, the solution was added 10mL of ethyl acetate, the reaction solution was washed with aqueous ammonium chloride the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到49mg(0.29mmol)标题化合物,收率18%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 49mg (0.29mmol) of the title compound in a yield of 18%.

[0312] 质量(EI)236(M++1) [0312] mass (EI) 236 (M ++ 1)

[0313] (4)合成4-氨基-2-氟-丁酸甲酯盐酸盐 [0313] (4) Synthesis of 4-amino-2-fluoro - butyric acid methyl ester hydrochloride

[0314] 除了利用上述步骤(3)获得的50mg(0.21mmol)4-叔-丁氧基羰基氨基-2-氟-丁酸甲酯之外,以制备1(4)相同的方式获得17mg(0.099mmol)标题化合物,收率47%。 [0314] In addition to the above-described step (3) obtained 50mg (0.21mmol) 4- tert - butoxycarbonylamino-2-fluoro - methyl butyrate addition, in the same manner as in Preparation 1 (4) to obtain 17mg ( 0.099 mmol) of the title compound in 47% yield.

[0315] NMR:1H-NMR(CD3OD)δ5.24~5.20(0.5H,m),5.15~4.95(0.5H,m),3.81(3H,s),3.21~3.08(2H,m),2.40~2.10(2H,m) [0315] NMR: 1H-NMR (CD3OD) δ5.24 ~ 5.20 (0.5H, m), 5.15 ~ 4.95 (0.5H, m), 3.81 (3H, s), 3.21 ~ 3.08 (2H, m), 2.40 ~ 2.10 (2H, m)

[0316] 质量(EI)172(M++1) [0316] mass (EI) 172 (M ++ 1)

[0317] 制备4:合成5-氨基-2-氟-戊酸甲酯盐酸盐 [0317] Preparation 4: Synthesis of 5-amino-2-fluoro - pentanoic acid methyl ester hydrochloride

[0318] (1)合成2-氧代-哌啶-1-羧酸叔-丁酯 [0318] (1) Synthesis of 2-oxo - piperidine-1-carboxylic acid tert - butyl ester

[0319] 除了利用1g(10.08mmol)2-哌啶酮之外,以制备3(1)相同方式,获得1.17g(8.88mmol)标题化合物,收率88%。 [0319] Besides using 1g (10.08mmol) 2- piperidone addition to (1) the same manner as Preparation 3 to give 1.17g (8.88mmol) of the title compound in 88% yield.

[0320] NMR:1H-NMR(CDCl3)δ3.67~3.64(2H,m),2.52~2.49(2H,m),1.86~1.78(4H,m),1.53(9H,s) [0320] NMR: 1H-NMR (CDCl3) δ3.67 ~ 3.64 (2H, m), 2.52 ~ 2.49 (2H, m), 1.86 ~ 1.78 (4H, m), 1.53 (9H, s)

[0321] 质量(EI)200(M++1) [0321] mass (EI) 200 (M ++ 1)

[0322] (2)合成3-氟-2-氧代-哌啶-1-羧酸叔-丁酯 [0322] (2) Synthesis of 3-fluoro-2-oxo - piperidine-1-carboxylic acid tert - butyl ester

[0323] 除了利用上述步骤(1)获得的300mg(1.5mmol)2-氧代-哌啶-1-羧酸叔-丁酯之外,以制备3(2)相同的方式,获得160mg(0.73mmol)标题化合物,收率48%。 [0323] 300mg except for using the above-described step (1) obtained in (1.5mmol) 2- oxo - piperidine-1-carboxylic acid tert - butyl ester addition to Preparation 3 (2) in the same manner to obtain 160mg (0.73 mmol) of the title compound in 48% yield.

[0324] NMR:1H-NMR(CDCl3)δ5.03~4.75(1H,m),3.75~3.55(2H,m),2.35~2.22(1H,m),2.05~1.78(3H,m),1.54(9H,s) [0324] NMR: 1H-NMR (CDCl3) δ5.03 ~ 4.75 (1H, m), 3.75 ~ 3.55 (2H, m), 2.35 ~ 2.22 (1H, m), 2.05 ~ 1.78 (3H, m), 1.54 (9H, s)

[0325] 质量(EI)218(M++1) [0325] mass (EI) 218 ​​(M ++ 1)

[0326] (3)合成5-叔-丁氧基羰基氨基-2-氟-戊酸甲酯 [0326] (3) Synthesis of 5-tert - butoxycarbonylamino-2-fluoro - pentanoic acid methyl ester

[0327] 除了利用上述步骤(2)的160mg(0.73mmol)3-氟-2-氧代-哌啶-1-羧酸叔-丁酯之外,以制备3(3)相同的方式,获得56mg(0.22mmol)标题化合物,收率30%。 [0327] In addition to the above steps (2) 160mg (0.73mmol) 3- fluoro-2-oxo - piperidine-1-carboxylic acid tert - butyl ester addition, in the same manner as Preparation 3 (3) to give 56mg (0.22mmol) of the title compound in 30% yield.

[0328] NMR:1H-NMR(CDCl3)δ5.02~4.87(1H,m),4.63(1H,brs),3.80(3H,s),3.25~3.05(2H,m),1.99~1.88(2H,m),1.72~1.64(2H,m),1.44(9H,s) [0328] NMR: 1H-NMR (CDCl3) δ5.02 ~ 4.87 (1H, m), 4.63 (1H, brs), 3.80 (3H, s), 3.25 ~ 3.05 (2H, m), 1.99 ~ 1.88 (2H , m), 1.72 ~ 1.64 (2H, m), 1.44 (9H, s)

[0329] 质量(EI)250(M++1) [0329] mass (EI) 250 (M ++ 1)

[0330] (4)合成5-氨基-2-氟-戊酸甲酯盐酸盐 [0330] (4) Synthesis of 5-amino-2-fluoro - pentanoic acid methyl ester hydrochloride

[0331] 除了利用上述步骤(3)的56mg(0.224mmol)5-叔-丁氧基羰基氨基-2-氟-戊酸甲酯之外,以制备1(4)相同的方式,获得40mg(0.21mmol)标题化合物,收率95%。 [0331] In addition to the above-described step (3) of 56mg (0.224mmol) 5- tert - butoxycarbonylamino-2-fluoro - pentanoic acid methyl ester addition to 1 (4) was prepared in the same manner to obtain 40mg ( 0.21 mmol) of the title compound in a yield of 95%.

[0332] NMR:1H-NMR(CDCl3)δ5.15~4.95(1H,m),3.81(3H,s),3.00~2.90(2H,m),2.10~1.73(4H,m) [0332] NMR: 1H-NMR (CDCl3) δ5.15 ~ 4.95 (1H, m), 3.81 (3H, s), 3.00 ~ 2.90 (2H, m), 2.10 ~ 1.73 (4H, m)

[0333] 质量(EI)186(M++1) [0333] mass (EI) 186 (M ++ 1)

[0334] 制备5:合成4-氨基-2-甲基-丁酸甲酯盐酸盐 Preparation of [0334] 5: Synthesis of 4-amino-2-methyl - butyric acid methyl ester hydrochloride

[0335] (1)合成3-甲基-2-氧代-吡咯烷-1-羧酸叔-丁酯 [0335] (1) Synthesis of 3-methyl-2-oxo - pyrrolidine-1-carboxylic acid tert - butyl ester

[0336] 将300mg(1.61mmol)2-氧代-吡咯烷-1-羧酸叔-丁酯溶解于四氢呋喃,然后冷却至-78℃。 [0336] A 300mg (1.61mmol) 2- oxo - pyrrolidine-1-carboxylic acid tert - butyl ester was dissolved in tetrahydrofuran and then cooled to -78 ℃. 向所得溶液滴加1.7mL(1.7mmol)1.0M双(三甲基甲硅烷基)氨化锂四氢呋喃溶液,接着搅拌1小时。 Lithium amide solution in tetrahydrofuran was added dropwise to the resulting solution 1.7mL (1.7mmol) 1.0M bis (trimethylsilyl group), followed by stirring for 1 hour. 向其中滴加0.19mL(3.05mmol)碘代甲烷。 Thereto was added dropwise 0.19 mL (3.05 mmol) of iodomethane. 其后,温度逐渐升高至-30℃,2小时。 Thereafter, the temperature was gradually raised to -30 ℃, 2 hours. 向溶液加入50mL乙酸乙酯,反应液以氯化铵水溶液洗涤,有机层用无水硫酸镁干燥。 50mL of ethyl acetate was added to the solution, the reaction was washed with aqueous ammonium chloride, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到130mg(0.65mmol)标题化合物,收率40%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 130mg (0.65mmol) of the title compound in 40% yield.

[0337] NMR:1H-NMR(CDCl3)δ3.79~3.74(1H,m),3.61~3.54(1H,m),2.59~2.53(1H,m),2.25~2.17(1H,m),1.67~1.59(1H,m),1.53(9H,s),1.20(3H,d,J=12Hz) [0337] NMR: 1H-NMR (CDCl3) δ3.79 ~ 3.74 (1H, m), 3.61 ~ 3.54 (1H, m), 2.59 ~ 2.53 (1H, m), 2.25 ~ 2.17 (1H, m), 1.67 ~ 1.59 (1H, m), 1.53 (9H, s), 1.20 (3H, d, J = 12Hz)

[0338] 质量(EI)200(M++1) [0338] mass (EI) 200 (M ++ 1)

[0339] (2)合成4-叔-丁氧基羰基氨基-2-甲基-丁酸甲酯 [0339] (2) Synthesis of 4-tert - butoxycarbonylamino-2-methyl - butyric acid methyl ester

[0340] 除了利用上述步骤(1)获得的130mg(0.65mmol)3-甲基-2-氧代-吡咯烷-1-羧酸叔-丁酯之外,以制备3(3)相同的方式,获得120mg(0.51mmol)标题化合物,收率78%。 Butyl way than to prepare 3 (3) the same - [0340] 130mg (0.65mmol) in addition to the above steps (1) to obtain 3-methyl-2-oxo - pyrrolidine-1-carboxylic acid tert to give 120mg (0.51mmol) of the title compound in 78% yield.

[0341] NMR:1H-NMR(CDCl3)δ4.58(1H,brs),3.68(3H,s),3.17~3.14(2H,m),2.55~2.47(1H,m),1.89~1.80(1H,m),1.67~1.60(1H,m),1.44(9H,s),1.19(3H,d,J=4Hz) [0341] NMR: 1H-NMR (CDCl3) δ4.58 (1H, brs), 3.68 (3H, s), 3.17 ~ 3.14 (2H, m), 2.55 ~ 2.47 (1H, m), 1.89 ~ 1.80 (1H , m), 1.67 ~ 1.60 (1H, m), 1.44 (9H, s), 1.19 (3H, d, J = 4Hz)

[0342] 质量(EI)232(M++1) [0342] mass (EI) 232 (M ++ 1)

[0343] (3)合成4-氨基-2-甲基-丁酸甲酯盐酸盐 [0343] (3) Synthesis of 4-amino-2-methyl - butyric acid methyl ester hydrochloride

[0344] 除了利用上述步骤(2)获得的120mg(0.51mmol)4-叔-丁氧基羰基氨基-2-甲基-丁酸甲酯之外,以制备1(4)相同的方式,获得80mg(0.47mmol)标题化合物,收率92%。 [0344] In addition to the above steps (2) 120mg (0.51mmol) of 4-tert - butoxycarbonylamino-2-methyl - butyric acid methyl ester addition, prepared in the same manner as Example 1 (4), 80mg (0.47mmol) of the title compound in 92% yield.

[0345] NMR:1H-NMR(CD3OD)δ3.70(3H,s),3.05~2.90(2H,m),2.65~2.55(1H,m),2.05~1.70(2H,m),1.23(3H,d,J=6Hz) [0345] NMR: 1H-NMR (CD3OD) δ3.70 (3H, s), 3.05 ~ 2.90 (2H, m), 2.65 ~ 2.55 (1H, m), 2.05 ~ 1.70 (2H, m), 1.23 (3H , d, J = 6Hz)

[0346] 质量(EI)168(M++1) [0346] mass (EI) 168 (M ++ 1)

[0347] 制备6:合成4-氨基-3-甲基-2-丁烯酸甲酯盐酸盐 [0347] Preparation 6: Synthesis of 4-amino-3-methyl-2-butenoate hydrochloride

[0348] (1)合成(2-羟基-丙基)-氨基甲酸叔-丁酯 [0348] (1) Synthesis of (2-hydroxy - propyl) - carbamic acid tert - butyl ester

[0349] 将1g(13.3mmol)1-氨基-丙烷-2-醇溶解于40mL甲醇和10mL水,然后向其中加入3.7g(16.9mmol)二碳酸二-叔-丁酯,接着室温下搅拌3小时。 [0349] A 1g (13.3mmol) 1--amino - 2-ol was dissolved in 40mL of methanol and 10mL of water, then added 3.7g (16.9mmol) di - tert - butyl ester, followed by stirring at room temperature for 3 hour. 向溶液加入200mL乙酸乙酯,反应液以水洗涤,然后有机层用无水硫酸镁干燥。 200mL of ethyl acetate was added to the solution, the reaction was washed with water, then the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到2.24g(12.8mmol)标题化合物,收率96%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 2.24g (12.8mmol) of the title compound in a yield of 96%.

[0350] NMR:1H-NMR(CDCl3)δ4.91(1H,brs),3.95~3.85(1H,m),3.30~3.22(1H,m),3.05~2.95(1H,m),1.43(9H,s),1.16(3H,d,J=4Hz)质量(EI)176(M++1) [0350] NMR: 1H-NMR (CDCl3) δ4.91 (1H, brs), 3.95 ~ 3.85 (1H, m), 3.30 ~ 3.22 (1H, m), 3.05 ~ 2.95 (1H, m), 1.43 (9H , s), 1.16 (3H, d, J = 4Hz) mass (EI) 176 (M ++ 1)

[0351] (2)合成(2-氧代-丙基)-氨基甲酸叔-丁酯 [0351] (2) Synthesis of (2-oxo - propyl) - carbamic acid tert - butyl ester

[0352] 将上述步骤(1)获得的2.24g(12.7mmol)(2-羟基-丙基)-氨基甲酸叔-丁酯溶解于30mL二氯甲烷,然后滴加3.6mL(25.7mmol)三乙胺。 2.24g [0352] The above step (1) obtained in (12.7mmol) (2- hydroxy - propyl) - carbamic acid tert - butyl ester was dissolved in 30mL dichloromethane and then added dropwise 3.6 mL (25.7 mmol) triethylamine amine. 向所得溶液加入6.05g(19mmol)50%吡啶三氧化硫溶解于15mL二甲基亚砜的溶液。 Was added 6.05g (19mmol) 50% pyridine sulfur trioxide dissolved in 15mL of dimethyl sulfoxide solution was added to the resulting solution. 6小时之后,向其中加入200mL乙酸乙酯,反应液以水洗涤,然后有机层用无水硫酸镁干燥。 After 6 hours, thereto was added 200mL of ethyl acetate, the reaction was washed with water, then the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到1.15g(6.64mmol)标题化合物,收率52%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 1.15g (6.64mmol) of the title compound in 52% yield.

[0353] NMR:1H-NMR(CDCl3)δ5.20(1H,brs),4.05~4.00(2H,m),2.17(3H,s),1.43(9H,s) [0353] NMR: 1H-NMR (CDCl3) δ5.20 (1H, brs), 4.05 ~ 4.00 (2H, m), 2.17 (3H, s), 1.43 (9H, s)

[0354] 质量(EI)174(M++1) [0354] mass (EI) 174 (M ++ 1)

[0355] (3)合成顺-4-叔-丁氧基羰基氨基-3-甲基-2-丁烯酸甲酯 [0355] (3) Synthesis of cis-4-tert - butoxycarbonylamino-3-methyl-2-butenoate

[0356] 将上述步骤(2)获得的500mg(2.88mmol)(2-氧代-丙基)-氨基甲酸叔-丁酯溶解于8mL苯,然后向其中加入1.45g(4.33mmol)(三苯基磷亚苯胺(phosphoranilidene))乙酸甲酯和35mg(0.28mmol)苯甲酸。 [0356] The above step (2) obtained 500mg (2.88mmol) (2- oxo - propyl) - carbamic acid tert - butyl ester was dissolved in 8mL of benzene, and thereto was added 1.45g (4.33mmol) (triphenyl phosphonium alkylene aniline (phosphoranilidene)) acetate and 35mg (0.28mmol) of benzoic acid. 反应液加热至80℃,3小时。 The reaction was heated to 80 ℃, 3 hours. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到54mg(6.64mmol)标题化合物,收率23%,和301mg(1.31mmol)反式化合物,收率45%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 54mg (6.64mmol) of the title compound in 23% yield, and 301mg (1.31mmol) of trans compound in a yield of 45%.

[0357] NMR:1H-NMR(CDCl3)δ5.77(1H,s),5.17(1H,brs),4.16(2H,d,J=6.4Hz),3.69(3H,s),2.05(3H,s),1.44(9H,s) [0357] NMR: 1H-NMR (CDCl3) δ5.77 (1H, s), 5.17 (1H, brs), 4.16 (2H, d, J = 6.4Hz), 3.69 (3H, s), 2.05 (3H, s), 1.44 (9H, s)

[0358] 质量(EI)230(M++1) [0358] mass (EI) 230 (M ++ 1)

[0359] (4)合成4-氨基-3-甲基-2-丁烯酸甲酯盐酸盐 [0359] (4) Synthesis of 4-amino-3-methyl-2-butenoate hydrochloride

[0360] 除了利用上述步骤(3)获得的54mg(0.235mmol)顺-4-叔-丁氧基羰基氨基-3-甲基-2-丁烯酸甲酯之外,以制备1(4)相同的方式,获得30mg(0.23mmol)标题化合物,收率97%。 [0360] 54mg except for using the above-described step (3) obtained in (0.235 mmol) of cis-4-tert - butoxycarbonylamino than methyl-2-amino-3-butenoate, prepared in 1 (4) the same manner, 30mg (0.23mmol) of the title compound in a yield of 97%.

[0361] NMR:1H-NMR(CD3OD)δ6.05(1H,s),4.00(2H,s),3.72(3H,s),3.29~3.28(2H,m),2.05(3H,s) [0361] NMR: 1H-NMR (CD3OD) δ6.05 (1H, s), 4.00 (2H, s), 3.72 (3H, s), 3.29 ~ 3.28 (2H, m), 2.05 (3H, s)

[0362] 质量(EI)130(M++1) [0362] mass (EI) 130 (M ++ 1)

[0363] 制备7:合成(R)-5-氨基-4-甲基-戊酸甲酯盐酸盐 [0363] Preparation 7: Synthesis of (R) -5- amino-4-methyl - pentanoic acid methyl ester hydrochloride

[0364] (1)合成(S)-3-甲磺酰氧基-2-甲基-丙酸甲酯 [0364] (1) Synthesis of (S) -3- methanesulfonyloxy-2-methyl - propionic acid methyl ester

[0365] 将3g(25.3mmol)(S)-3-羟基-2-甲基-丙酸甲酯溶解于二氯甲烷50mL,然后向其中滴加5.3mL(37.9mmol)三乙胺。 [0365] The 3g (25.3mmol) (S) -3- hydroxy-2-methyl - propionic acid methyl ester was dissolved in dichloromethane 50mL, and then added dropwise 5.3mL (37.9mmol) of triethylamine. 其后,0℃下向溶液加入2.16mL(27.9mmol)甲磺酰氯。 Thereafter, at 0 ℃ was added 2.16mL (27.9mmol) of methanesulfonyl chloride to the solution. 1小时之后,向溶液加入200mL乙酰乙酸乙酯,然后反应液以水洗涤,然后有机层用无水硫酸镁干燥。 After 1 hour, the solution was added 200mL of ethyl acetoacetate, and the reaction solution was washed with water, then the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到4.97g(25.3mmol)标题化合物,收率100%. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 4.97g (25.3mmol) of the title compound, yield 100%.

[0366] 质量(EI)197(M++1) [0366] mass (EI) 197 (M ++ 1)

[0367] (2)合成(S)-3-叠氮基-2-甲基-丙酸甲酯 [0367] (2) Synthesis of (S) -3- azido-2-methyl - propionic acid methyl ester

[0368] 将上述步骤(2)获得的4.97g(25.3mmol)(S)-3-甲磺酰氧基-2-甲基-丙酸甲酯溶解于40mL二甲基甲酰胺,然后向其中加入5g(76.8mmol)叠氮化钠,接着60℃下搅拌24小时。 [0368] The above step (2) obtained in 4.97g (25.3mmol) (S) -3- methanesulfonyloxy-2-methyl - propionic acid methyl ester was dissolved in 40mL of dimethylformamide, and then thereto was added 5g (76.8mmol) of sodium azide, followed by stirring at 60 ℃ 24 hours. 向溶液加入200mL乙酰乙酸乙酯,反应液以水洗涤,然后有机层用无水硫酸镁干燥。 200mL ethyl acetoacetate was added to the solution, the reaction was washed with water, then the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到3.5g(24.4mmol)标题化合物,收率96%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 3.5g (24.4mmol) of the title compound in a yield of 96%.

[0369] NMR:1H-NMR(CDCl3)δ3.71(3H,s),3.54~3.52(1H,m),3.40~3.30(1H,m),2.80~2.65(1H,m),1.20(3H,d,J=7.2Hz) [0369] NMR: 1H-NMR (CDCl3) δ3.71 (3H, s), 3.54 ~ 3.52 (1H, m), 3.40 ~ 3.30 (1H, m), 2.80 ~ 2.65 (1H, m), 1.20 (3H , d, J = 7.2Hz)

[0370] 质量(EI)144(M++1) [0370] mass (EI) 144 (M ++ 1)

[0371] (3)合成(S)-3-叔-丁氧基羰基氨基-2-甲基-丙酸甲酯 [0371] (3) Synthesis of (S) -3- tert - butoxycarbonylamino-2-methyl - propionic acid methyl ester

[0372] 将上述步骤(2)获得的3.9g(26.8mmol)(S)-3-叠氮基-2-甲基-丙酸甲酯溶解于50mL甲醇,接着加入8.8g(40.3mmol)二碳酸二-叔-丁酯。 [0372] The above step (2) obtained 3.9g (26.8mmol) (S) -3- azido-2-methyl - propionic acid methyl ester was dissolved in 50mL of methanol, followed by addition of 8.8g (40.3mmol) two di - t - butyl ester. 反应利用40mg 20%钯/碳,在氢气气氛下进行9小时。 The reaction using 40mg 20% ​​palladium / carbon under a hydrogen atmosphere for 9 hours. 反应液经Celite过滤,减压下蒸馏,然后通过柱层析纯化残留物,得到2.6g(11.9mmol)标题化合物,收率44%。 The reaction was filtered through of Celite, evaporated under reduced pressure, and the residue was purified by column chromatography to give 2.6g (11.9mmol) of the title compound in 44% yield.

[0373] NMR:1H-NMR(CDCl3)δ4.92(1H,brs),3.70(3H,s),3.31~3.20(2H,m),2.70~2.55(1H,m),1.43(9H,s),1.15(3H,d,J=12Hz) [0373] NMR: 1H-NMR (CDCl3) δ4.92 (1H, brs), 3.70 (3H, s), 3.31 ~ 3.20 (2H, m), 2.70 ~ 2.55 (1H, m), 1.43 (9H, s ), 1.15 (3H, d, J = 12Hz)

[0374] 质量(EI)218(M++1) [0374] mass (EI) 218 ​​(M ++ 1)

[0375] (4)合成(S)-(3-羟基-2-甲基-丙基)-氨基甲酸叔-丁酯 [0375] (4) Synthesis of (S) - (3- hydroxy-2-methyl - propyl) - carbamic acid tert - butyl ester

[0376] 将上述步骤(3)获得的500mg(2.30mmol)(S)-3-叔-丁氧基羰基氨基-2-甲基-丙酸甲酯溶解于30mL四氢呋喃,然后0℃下向其中缓慢加入262mg(6.9mmol)氢化锂铝。 [0376] The above step (3) obtained 500mg (2.30mmol) (S) -3- tert - butoxycarbonylamino-2-methyl - propionic acid methyl ester was dissolved in 30mL of tetrahydrofuran, and then thereto at 0 ℃ was slowly added 262mg (6.9mmol) of lithium aluminum hydride. 温热至室温之后,反应进行4小时。 After warming to room temperature, the reaction was carried out for 4 hours. 反应液冷却至0℃,然后向其中缓慢加入0.26mL水、0.26mL氢氧化钠溶液和0.78mL水。 The reaction solution was cooled to 0 ℃, then 0.26 mL water was slowly added thereto, 0.26mL 0.78mL sodium hydroxide solution and water. 反应液经Celite过滤,减压下蒸馏,然后通过柱层析纯化残留物,得到430mg(2.27mmol)标题化合物,收率98%。 The reaction was filtered through Celite, distilled under reduced pressure, and the residue was purified by column chromatography to give 430mg (2.27mmol) of the title compound in a yield of 98%.

[0377] NMR:1H-NMR(CDCl3)δ4.78(1H,brs),3.55~3.50(1H,m),3.33~3.20(2H,m),3.05~2.98(1H,m),1.75~1.65(1H,m),1.46(9H,s),0.87(3H,d,J=12Hz) [0377] NMR: 1H-NMR (CDCl3) δ4.78 (1H, brs), 3.55 ~ 3.50 (1H, m), 3.33 ~ 3.20 (2H, m), 3.05 ~ 2.98 (1H, m), 1.75 ~ 1.65 (1H, m), 1.46 (9H, s), 0.87 (3H, d, J = 12Hz)

[0378] 质量(EI)190(M++1) [0378] mass (EI) 190 (M ++ 1)

[0379] (5)合成(S)-(2-甲基-3-氧代-丙基)-氨基甲酸叔-丁酯 [0379] (5) Synthesis of (S) - (2- methyl-3-oxo - propyl) - carbamic acid tert - butyl ester

[0380] 除了利用上述步骤(4)获得的430mg(2.27mmol)(S)-(3-羟基-2-甲基-丙基)-氨基甲酸叔-丁酯之外,以制备6-(2)相同的方式,获得423mg(2.26mmol)标题化合物,收率99%。 [0380] 430mg (2.27mmol) except for using the above-described step (4) obtained in (S) - (3- hydroxy-2-methyl - propyl) - carbamic acid tert - butyl ester addition to the preparation of 6- (2 ) in the same manner to obtain 423mg (2.26mmol) of the title compound in 99% yield.

[0381] 质量(EI)188(M++1) [0381] mass (EI) 188 (M ++ 1)

[0382] (6)合成(R)-5-叔-丁氧基羰基氨基-4-甲基-2-戊烯酸甲酯 [0382] (6) Synthesis of (R) -5- tert - butoxycarbonylamino-4-methyl-2-pentenoate

[0383] 除了利用上述步骤(5)获得的423mg(2.26mmol)(S)-(2-甲基-3-氧代-丙基)-氨基甲酸叔-丁酯之外,以制备6-(3)相同的方式,获得380mg(2.26mmol)标题化合物,收率99%。 [0383] 423mg (2.26mmol) (S) except for using the above-described step (5) obtained in - (2-methyl-3-oxo - propyl) - carbamic acid tert - butyl ester addition to the preparation of 6- ( 3) in the same manner to obtain 380mg (2.26mmol) of the title compound in 99% yield.

[0384] NMR:1H-NMR(CDCl3)δ6.84(1H,dd,J=15Hz,10Hz),5.84(1H,d,J=15Hz),4.55(1H,brs),3.72(3H,s),3.25~3.15(1H,m),3.06~3.00(1H,m),2.54~2.47(1H,m),1.42(9H,s),1.03(3H,d,J=15Hz) [0384] NMR: 1H-NMR (CDCl3) δ6.84 (1H, dd, J = 15Hz, 10Hz), 5.84 (1H, d, J = 15Hz), 4.55 (1H, brs), 3.72 (3H, s) , 3.25 ~ 3.15 (1H, m), 3.06 ~ 3.00 (1H, m), 2.54 ~ 2.47 (1H, m), 1.42 (9H, s), 1.03 (3H, d, J = 15Hz)

[0385] 质量(EI)244(M++1) [0385] mass (EI) 244 (M ++ 1)

[0386] (7)合成(R)-5-叔-丁氧基羰基氨基-4-甲基-戊酸甲酯 [0386] (7) Synthesis of (R) -5- tert - butoxycarbonylamino-4-methyl - pentanoic acid methyl ester

[0387] 将上述步骤(6)获得的370mg(2.26mmol)(R)-5-叔-丁氧基羰基氨基-4-甲基-2-戊烯酸甲酯溶解于50mL甲醇。 [0387] 370mg in the above step (6) obtained in (2.26mmol) (R) -5- tert - butoxycarbonylamino-4-methyl-2-pentenoate was dissolved in 50mL of methanol. 反应利用40mg 20%氢氧化钯,在氢气氛下进行9小时,反应液经Celite过滤。 The reaction using 40mg 20% ​​palladium hydroxide, under a hydrogen atmosphere for 9 hours, the reaction was filtered through Celite. 减压下蒸馏掉过滤液,然后通过柱层析纯化残留物,得到310mg(1.26mmol)标题化合物,收率55%。 The filtrate was then distilled off under residue was purified by column chromatography to give 310mg (1.26mmol) of the title compound in a yield of 55% under reduced pressure.

[0388] NMR:1H-NMR(CDCl3)δ4.87(1H,brs),3.67(3H,s),3.05~2.96(2H,m),2.39~2.27(2H,m),1.75~1.40(3H,m),1.44(9H,s),0.87(3H,d,J=12Hz) [0388] NMR: 1H-NMR (CDCl3) δ4.87 (1H, brs), 3.67 (3H, s), 3.05 ~ 2.96 (2H, m), 2.39 ~ 2.27 (2H, m), 1.75 ~ 1.40 (3H , m), 1.44 (9H, s), 0.87 (3H, d, J = 12Hz)

[0389] 质量(EI)246(M++1) [0389] mass (EI) 246 (M ++ 1)

[0390] (8)合成(R)-5-氨基-4-甲基-戊酸甲酯盐酸盐 [0390] (8) Synthesis of (R) -5- amino-4-methyl - pentanoic acid methyl ester hydrochloride

[0391] 除了用上述步骤(7)获得的310mg(1.26mmol)(R)-5-叔-丁氧基羰基氨基-4-甲基-戊酸甲酯之外,以制备1-(4)相同的方式,获得220mg(1.21mmol)标题化合物。 [0391] In addition to 310mg (7) obtained in the above step (1.26mmol) (R) -5- tert - butoxycarbonylamino-4-methyl - pentanoic acid methyl ester addition to the preparation of 1- (4) in the same manner to obtain 220mg (1.21mmol) of the title compound.

[0392] NMR:1H-NMR(CD3OD)δ3.87(3H,s),2.96~2.91(1H,m),2.81~2.76(1H,m),2.47~2.40(2H,m),1.88~1.76(2H,m),1.56~1.50(1H,m),1.04(3H,d,J=6.4Hz) [0392] NMR: 1H-NMR (CD3OD) δ3.87 (3H, s), 2.96 ~ 2.91 (1H, m), 2.81 ~ 2.76 (1H, m), 2.47 ~ 2.40 (2H, m), 1.88 ~ 1.76 (2H, m), 1.56 ~ 1.50 (1H, m), 1.04 (3H, d, J = 6.4Hz)

[0393] 质量(EI)182(M++1) [0393] mass (EI) 182 (M ++ 1)

[0394] 制备8:合成5-氨基-3-甲基-戊酸甲酯盐酸盐 [0394] Preparation 8: Synthesis of 5-Amino-3-methyl - pentanoic acid methyl ester hydrochloride

[0395] (1)合成4-甲基-哌啶-1-羧酸叔-丁酯 [0395] (1) Synthesis of 4-methyl - piperidine-1-carboxylic acid tert - butyl ester

[0396] 除了用2g(20.1mmol)4-甲基哌啶之外,以制备6-(1)相同的方式获得3.5g(17.5mmol)标题化合物,收率87%。 [0396] In addition to (20.1mmol) 4- methylpiperidine with 2g, prepared 6- (1) in the same manner to obtain 3.5g (17.5mmol) of the title compound in 87% yield.

[0397] 质量(EI)200(M++1) [0397] mass (EI) 200 (M ++ 1)

[0398] (2)合成4-甲基-2-氧代-哌啶-1-羧酸叔-丁酯 [0398] (2) Synthesis of 4-methyl-2-oxo - piperidine-1-carboxylic acid tert - butyl ester

[0399] 将上述步骤(1)获得的1g(5.02mmol)4-甲基-哌啶-1-羧酸叔-丁酯溶解于70mL乙酸乙酯。 [0399] The above step (1) 1g (5.02mmol) of 4-methyl - piperidine-1-carboxylic acid tert - butyl ester was dissolved in 70mL ethyl acetate. 向所得溶液中滴加一溶液,在该溶液中,5.4g(25.2mmol)高碘酸钠和247mg(1.85mmol)二氧化钌溶解于40mL水。 Was added dropwise a solution to the resulting solution, the solution, 5.4g (25.2mmol) of sodium periodate and 247 mg (1.85 mmol) of ruthenium dioxide were dissolved in 40mL water. 3小时之后,向其中加入5%硫代硫酸钠,所得溶液以乙酸乙酯萃取,然后有机层用无水硫酸镁干燥。 After 3 hours, and thereto was added 5% sodium thiosulfate and the resulting solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到750mg(3.52mmol)标题化合物,收率70%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 750mg (3.52mmol) of the title compound in 70% yield.

[0400] NMR:1H-NMR(CDCl3)δ4.11~3.77(1H,m),3.53~3.49(1H,m),2.62~2.56(1H,m),2.15~1.90(3H,m),1.49(9H,s),1.48~1.26(1H,m),1.02(3H,d J=4Hz) [0400] NMR: 1H-NMR (CDCl3) δ4.11 ~ 3.77 (1H, m), 3.53 ~ 3.49 (1H, m), 2.62 ~ 2.56 (1H, m), 2.15 ~ 1.90 (3H, m), 1.49 (9H, s), 1.48 ~ 1.26 (1H, m), 1.02 (3H, d J = 4Hz)

[0401] 质量(EI)214(M++1) [0401] mass (EI) 214 (M ++ 1)

[0402] (3)合成5-叔-丁氧基羰基氨基-3-甲基-戊酸甲酯 [0402] (3) Synthesis of 5-tert - butoxycarbonylamino-3-methyl - pentanoic acid methyl ester

[0403] 除了用上述步骤(2)获得的368mg(1.72mmol)4-甲基-2-氧代-哌啶-1-羧酸叔-丁酯之外,以制备3-(3)相同的方式,获得410mg(1.67mmol)标题化合物,收率97%。 [0403] In addition to 368mg above step (2) obtained in (1.72mmol) 4- methyl-2-oxo - piperidine-1-carboxylic acid tert - butyl ester addition to the preparation of 3 (3) of the same manner, 410mg (1.67mmol) of the title compound in a yield of 97%.

[0404] 1H NMR(CDCl3)δ4.5-4.6(1H,br s),3.65(3H,s),3.0-3.2(2H,m),2.3(1H,m),2.15(1H,m),2.0(1H,m),1.4-1.5(2H,m),1.45(9H,s) [0404] 1H NMR (CDCl3) δ4.5-4.6 (1H, br s), 3.65 (3H, s), 3.0-3.2 (2H, m), 2.3 (1H, m), 2.15 (1H, m), 2.0 (1H, m), 1.4-1.5 (2H, m), 1.45 (9H, s)

[0405] 质量(m/e)268(M+Na) [0405] mass (m / e) 268 (M + Na)

[0406] (4)合成5-氨基-3-甲基-戊酸甲酯盐酸盐 [0406] (4) Synthesis of 5-amino-3-methyl - pentanoic acid methyl ester hydrochloride

[0407] 除了用上述步骤(3)获得的410mg(1.24mmol)5-叔-丁氧基羰基氨基-3-甲基-戊酸甲酯之外,以制备1-(4)相同的方式,获得226mg(1.24mmol)标题化合物,收率74%。 [0407] (1.24mmol) 5- tert 410mg above except that in step (3) obtained in - butoxycarbonylamino-3-methyl - pentanoic acid methyl ester addition to the preparation of 1- (4) in the same manner, to obtain 226mg (1.24mmol) of the title compound in 74% yield.

[0408] 1H NMR(CD3OD)δ3.65(3H,s),2.9-3.0(2H,m),2.34(1H,dd,J=15,7Hz),2.27(1H,dd,J=15,7Hz),2.0(1H,m),1.7(1H,m),1.54(1H,m),0.98(3H,d,J=7Hz) [0408] 1H NMR (CD3OD) δ3.65 (3H, s), 2.9-3.0 (2H, m), 2.34 (1H, dd, J = 15,7Hz), 2.27 (1H, dd, J = 15,7Hz ), 2.0 (1H, m), 1.7 (1H, m), 1.54 (1H, m), 0.98 (3H, d, J = 7Hz)

[0409] 质量(m/e)146(M+1) [0409] mass (m / e) 146 (M + 1)

[0410] 制备9:合成4-氨基甲基-5,5,5-三氟-戊酸甲酯盐酸盐 [0410] Preparation 9: Synthesis of 4-aminomethyl-5,5,5-trifluoro - pentanoic acid methyl ester hydrochloride

[0411] (1)合成5-三氟甲基-哌啶-2-酮 [0411] (1) Synthesis of 5-trifluoromethyl - piperidin-2-one

[0412] 1g(6.13mmol)5-三氟甲基-2-piridinol溶解于20mL乙酸。 [0412] 1g (6.13mmol) 5- trifluoromethyl -2-piridinol was dissolved in 20mL acetic acid. 反应用300mg氧化铂,在50psi氢(气)压力下进行9小时。 The reaction, carried out under 50psi of hydrogen (gas) pressure with 300mg of platinum oxide for 9 hours. 反应液经Celite过滤,减压下馏出,然后通过柱层析纯化残留物,得到920mg(5.50mmol)标题化合物,收率89%。 The reaction was filtered through Celite, distilled off under reduced pressure, and the residue was purified by column chromatography to give 920mg (5.50mmol) of the title compound in 89% yield.

[0413] NMR:1H-NMR(CDCl3)δ3.56~3.51(1H,m),3.42~3.36(1H,m),2.59~2.53(2H,m),2.45~2.41(1H,m),2.19~2.13(1H,m),1.95~1.87(1H,m) [0413] NMR: 1H-NMR (CDCl3) δ3.56 ~ 3.51 (1H, m), 3.42 ~ 3.36 (1H, m), 2.59 ~ 2.53 (2H, m), 2.45 ~ 2.41 (1H, m), 2.19 ~ 2.13 (1H, m), 1.95 ~ 1.87 (1H, m)

[0414] 质量(EI)168(M++1) [0414] mass (EI) 168 (M ++ 1)

[0415] (2)合成2-氧代-5-三氟甲基-哌啶-1-羧酸叔-丁酯 [0415] (2) Synthesis of 2-oxo-5-trifluoromethyl - piperidine-1-carboxylic acid tert - butyl ester

[0416] 将上述步骤(1)获得的1.3g(7.7mmol)of 5-三氟甲基-哌啶-2-酮溶解于10mL乙腈。 [0416] The above step (1) 1.3g (7.7mmol) of 5- trifluoromethyl obtained - piperidin-2-one was dissolved in 10mL of acetonitrile. 向溶液加入2.0g(14.3mmol)三乙胺、48mg(0.39mmol)二甲基氨基吡啶和1.8g(8.2mmol)二碳酸二-叔-丁酯。 Was added 2.0g (14.3mmol) of triethylamine, 48mg (0.39mmol) of dimethylaminopyridine and 1.8g (8.2mmol) to a solution of di - t - butyl ester. 80℃下搅拌4小时之后,向先前形成的溶液中加入100mL乙酸乙酯,反应液以水洗涤。 After stirring at 80 ℃ 4 h, the solution was added 100mL ethyl acetate previously formed in the reaction was washed with water. 有机层用无水硫酸镁干燥。 The organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,然后通过柱层析纯化残留物,得到669mg(2.5mmol)标题化合物,柱层析收率为32%。 The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 669mg (2.5mmol) of the title compound in 32% yield by column chromatography.

[0417] NMR:1H-NMR(CDCl3)δ4.09~3.97(1H,m),3.77~3.71(1H,m),2.70~2.47(3H,m),2.15~2.10(1H,m),1.97~1.89(1H,m),1,50(9H,s) [0417] NMR: 1H-NMR (CDCl3) δ4.09 ~ 3.97 (1H, m), 3.77 ~ 3.71 (1H, m), 2.70 ~ 2.47 (3H, m), 2.15 ~ 2.10 (1H, m), 1.97 ~ 1.89 (1H, m), 1,50 (9H, s)

[0418] 质量(EI)268(M++1) [0418] mass (EI) 268 (M ++ 1)

[0419] (3)合成4-(叔-丁氧基羰基氨基-甲基)-5,5,5-三氟-戊酸甲酯 [0419] (3) Synthesis of 4- (tert - butoxycarbonyl amino - methyl) -5,5,5-trifluoro - pentanoic acid methyl ester

[0420] 除了用上述步骤(2)获得的669mg(2.5mmol)2-氧代-5-三氟甲基-哌啶-1-羧酸叔-丁酯之外,以制备3-(3)相同的方式,获得500mg(1.67mmol)标题化合物,收率66%。 [0420] In addition to 669mg above step (2) obtained in (2.5mmol) 2- oxo-5-trifluoromethyl - piperidine-1-carboxylic acid tert - butyl ester addition to the preparation of 3 (3) in the same manner to obtain 500mg (1.67mmol) of the title compound, yield 66%.

[0421] NMR:1H-NMR(CDCl3)δ4.76(1H,s),3.68(3H,s),3.45~3.30(2H,m),2.55~2.48(2H,m),2.40~2.32(1H,m),2.00~1.95(1H,m),1.90~1.80(1H,m),1,43(9H,s) [0421] NMR: 1H-NMR (CDCl3) δ4.76 (1H, s), 3.68 (3H, s), 3.45 ~ 3.30 (2H, m), 2.55 ~ 2.48 (2H, m), 2.40 ~ 2.32 (1H , m), 2.00 ~ 1.95 (1H, m), 1.90 ~ 1.80 (1H, m), 1,43 (9H, s)

[0422] 质量(EI)300(M++1) [0422] mass (EI) 300 (M ++ 1)

[0423] (4)合成4-氨基甲基-5,5,5-三氟-戊酸甲酯盐酸盐 [0423] (4) Synthesis of 4-aminomethyl-5,5,5-trifluoro - pentanoic acid methyl ester hydrochloride

[0424] 除了用上述步骤(3)获得的500mg(1.67mmol)4-(叔-丁氧基羰基氨基-甲基)-5,5,5-三氟-戊酸甲酯之外,以制备1-(4)相同的方式,获得335mg(1.42mmol)标题化合物,收率85%。 [0424] In addition to 500mg (1.67mmol) by the above step (3) of 4- (tert - butoxycarbonyl amino - methyl) -5,5,5-trifluoro - pentanoic acid methyl ester addition to the preparation of 1- (4) in the same manner to obtain 335mg (1.42mmol) of the title compound in 85% yield.

[0425] NMR:1H-NMR(CDCl3)δ8.48(2H,s),3.69(3H,s),3.50~3.40(1H,m),3.30~3.15(1H,m),2.99~2.89(1H,m),2.65~2.52(2H,m),2.11~1.91(2H,m) [0425] NMR: 1H-NMR (CDCl3) δ8.48 (2H, s), 3.69 (3H, s), 3.50 ~ 3.40 (1H, m), 3.30 ~ 3.15 (1H, m), 2.99 ~ 2.89 (1H , m), 2.65 ~ 2.52 (2H, m), 2.11 ~ 1.91 (2H, m)

[0426] 质量(EI)236(M++1) [0426] mass (EI) 236 (M ++ 1)

[0427] 制备10:合成(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐 [0427] Preparation 10: Synthesis of (2-amino-1 - methyl-ethoxy) - acetate hydrochloride

[0428] (1)合成(2-叔-丁氧基羰基氨基-1-甲基-乙氧基)-乙酸乙酯 [0428] (1) Synthesis of (2-tert - butoxycarbonylamino-1-methyl - ethoxy) - ethyl

[0429] 将500mg(2.85mmol)(2-羟基-丙基)-氨基甲酸叔-丁酯溶解于10mL二氯乙烷,然后向反应中加入0.44mL(4.24mmol)重氮乙酸乙酯。 [0429] A 500mg (2.85mmol) (2- hydroxy - propyl) - carbamic acid tert - butyl ester was dissolved in 10mL of dichloroethane was added 0.44mL (4.24mmol) of ethyl diazoacetate to the reaction. 反应中加入38mg(0.085mmol)乙酸铑,然后加热至80℃,2小时。 The reaction was added 38mg (0.085mmol) of rhodium acetate, followed by heating to 80 ℃, 2 hours. 减压下蒸馏掉溶剂,并通过柱层析纯化残留物,得到381mg(1.45mmol)标题化合物,收率50%。 The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 381mg (1.45mmol) of the title compound in 50% yield.

[0430] NMR:1H-NMR(CDCl3)δ5.39(1H,s),4.23(2H,q,J=8Hz),4.09(1H,d,J=16Hz),4.00(1H,d,J=16Hz),3.60~3.35(1H,m),3.35~3.15(1H,m),3.10~3.04(1H,m),1.46(9H,s),1.31(3H,t,J=4Hz),1.16(3H,d,J=4Hz) [0430] NMR: 1H-NMR (CDCl3) δ5.39 (1H, s), 4.23 (2H, q, J = 8Hz), 4.09 (1H, d, J = 16Hz), 4.00 (1H, d, J = 16Hz), 3.60 ~ 3.35 (1H, m), 3.35 ~ 3.15 (1H, m), 3.10 ~ 3.04 (1H, m), 1.46 (9H, s), 1.31 (3H, t, J = 4Hz), 1.16 ( 3H, d, J = 4Hz)

[0431] 质量(EI)262(M++1) [0431] mass (EI) 262 (M ++ 1)

[0432] (2)合成(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐 [0432] (2) Synthesis of (2-amino-1 - methyl-ethoxy) - acetate hydrochloride

[0433] 除了用上述步骤(上述步骤(1)的381mg(1.45mmol)2-叔-丁氧基羰基氨基-1-甲基-乙氧基)-乙酸乙酯之外,以制备1-(4)相同的方式,获得130mg(0.65mmol)标题化合物,收率44%。 [0433] In addition to the above step (the above step (1) of 381mg (1.45mmol) 2- tert - butoxycarbonylamino-1-methyl-ethoxy) - - addition of ethyl acetate to prepare a 1- ( 4) in the same manner to obtain 130mg (0.65mmol) of the title compound in 44% yield.

[0434] NMR:1H-NMR(CDCl3)δ8.47(2H,s),4.23(2H,q,J=8Hz),4.22~3.99(2H,m),3.80~3.70(1H,m),3.25~3.20(1H,m),3.10~2.98(1H,m),1.29(3H,t,J=7.5Hz),1.20(3H,d,J=5Hz) [0434] NMR: 1H-NMR (CDCl3) δ8.47 (2H, s), 4.23 (2H, q, J = 8Hz), 4.22 ~ 3.99 (2H, m), 3.80 ~ 3.70 (1H, m), 3.25 ~ 3.20 (1H, m), 3.10 ~ 2.98 (1H, m), 1.29 (3H, t, J = 7.5Hz), 1.20 (3H, d, J = 5Hz)

[0435] 质量(EI)200(M++1) [0435] mass (EI) 200 (M ++ 1)

[0436] 制备11:合成5-氨基-3-三氟甲基-戊酸乙酯盐酸盐 [0436] Preparation 11: Synthesis of 5-amino-3-trifluoromethyl - pentanoic acid ethyl ester hydrochloride

[0437] (1)合成2-氧代-4-三氟甲基-哌啶-1-羧酸叔-丁酯 [0437] (1) Synthesis of 2-oxo-4-trifluoromethyl - piperidine-1-carboxylic acid tert - butyl ester

[0438] 将2.82g(3.2mmol)甲高碘酸钠(sodium methaperiodate)(NaIO4)溶解于20mL水,接着加入117mg(0.88mmol)氧化钌(RuO2)。 [0438] A 2.82g (3.2mmol) methyl sodium periodate (sodium methaperiodate) (NaIO4) was dissolved in 20mL of water, followed by addition of 117mg (0.88mmol) of ruthenium oxide (RuO2). 向反应中加入一溶液,在该溶液中660mg(2.6mmol)4-三氟甲基-哌啶-1-羧酸叔-丁酯溶解于35mL乙酸乙酯,接着搅拌2小时20分钟。 Was added a solution of the reaction, the solution 660mg (2.6mmol) 4- trifluoromethyl - piperidine-1-carboxylic acid tert - butyl ester was dissolved in 35mL ethyl acetate, followed by stirring for 2 hours 20 minutes. 反应液以过量乙酸乙酯稀释,并分别用水和NaCl水溶液洗涤一次,然后用无水硫酸镁干燥,并过滤。 The reaction solution was diluted with excess ethyl acetate, and washed with water and aqueous NaCl solution once, and then dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,残留物通过柱层析(2∶1己烷∶乙酸乙酯)纯化,得到0.63g标题化合物,收率90%。 Purification: (1 hexanes ethyl acetate), to give 0.63g of the title compound in a yield of 90% was distilled off the filtrate, the residue was purified by column chromatography under reduced pressure.

[0439] 1H NMR(CDCl3)δ3.86(1H,dd,J=13.5,5.5Hz),3.62(1H,m),2.6-2.8(2H,m),2.56(1H,dd,J=17,10Hz),2.1-2.2(1H,m),1.8-1.9(1H,m),1.53(9H,s) [0439] 1H NMR (CDCl3) δ3.86 (1H, dd, J = 13.5,5.5Hz), 3.62 (1H, m), 2.6-2.8 (2H, m), 2.56 (1H, dd, J = 17, 10Hz), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.53 (9H, s)

[0440] 质量(m/e)290(M+Na) [0440] mass (m / e) 290 (M + Na)

[0441] (2)合成5-叔-丁氧基羰基氨基-3-三氟甲基-戊酸乙酯 [0441] (2) Synthesis of 5-tert - butoxycarbonylamino-3-trifluoromethyl - pentanoic acid ethyl ester

[0442] 将上述步骤(1)获得的630mg(2.36mmol)2-氧代-4-三氟甲基-哌啶-1-羧酸叔-丁酯溶解于甲醇,然后向其中加入255mg(4.5mmol)乙醇钠,接着搅拌15分钟。 [0442] The above step (1) obtained 630mg (2.36mmol) 2- oxo-4-trifluoromethyl - piperidine-1-carboxylic acid tert - butyl ester was dissolved in methanol, and thereto was added 255mg (4.5 mmol) of sodium ethoxide, followed by stirring for 15 minutes. 浓缩后,反应以过量乙酸乙酯稀释,反应液分别用1N盐酸水溶液和NaCl水溶液洗涤一次,用无水硫酸镁干燥,并过滤。 After concentration, the reaction was diluted with excess ethyl acetate, the reaction solution were washed with 1N aqueous hydrochloric acid and aqueous NaCl solution once, dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,然后残留物通过柱层析纯化(5∶1己烷∶乙酸乙酯),得到0.48g标题化合物,收率65%。 The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography (5:1 hexanes: ethyl acetate) to give the title compound 0.48g, 65% yield.

[0443] 1H NMR(CDCl3)δ4.76(1H,br s),4.17(2H,q,J=7.0Hz),3.1-3.3(2H,m),2.7-2.8(1H,m),2.62(1H,dd,J=16,5Hz),2.4(1H,dd,J=16,8Hz),1.9(1H,m),1.6(1H,m),1.43(9H,s),1.26(3H,t,J=7.0Hz) [0443] 1H NMR (CDCl3) δ4.76 (1H, br s), 4.17 (2H, q, J = 7.0Hz), 3.1-3.3 (2H, m), 2.7-2.8 (1H, m), 2.62 ( 1H, dd, J = 16,5Hz), 2.4 (1H, dd, J = 16,8Hz), 1.9 (1H, m), 1.6 (1H, m), 1.43 (9H, s), 1.26 (3H, t , J = 7.0Hz)

[0444] 质量(m/e)336(M+Na) [0444] mass (m / e) 336 (M + Na)

[0445] (3)合成5-氨基-3-三氟甲基-戊酸乙酯盐酸盐 [0445] (3) Synthesis of 5-amino-3-trifluoromethyl - pentanoic acid ethyl ester hydrochloride

[0446] 将上述步骤(2)获得的477mg(1.5mmol)5-叔-丁氧基羰基氨基-3-三氟甲基-戊酸乙酯与乙酸乙酯/盐酸反应,接着搅拌35分钟。 [0446] The above step (2) 477mg obtained (1.5mmol) 5- tert - butoxycarbonylamino-3-trifluoromethyl - pentanoic acid ethyl ester / ethyl acetate to react with hydrochloric acid, followed by stirring for 35 minutes. 然后,反应液以二乙基醚浓缩并固化,得到0.220g标题化合物,收率68%。 Then, the reaction mixture was concentrated and solidified with diethyl ether to afford 0.220g of the title compound in 68% yield.

[0447] 1H NMR(CDCl3)δ4.16(2H,q,J=7.0Hz),3.04(2H,t,J=8.0Hz),2.9(1H,m),2.70(1H,dd,J=16,5Hz),2.55(1H,dd,J=17,8Hz),2.0-2.1(1H,m),1.8-1.9(1H,m),1.26(3H,t,J=7.0Hz) [0447] 1H NMR (CDCl3) δ4.16 (2H, q, J = 7.0Hz), 3.04 (2H, t, J = 8.0Hz), 2.9 (1H, m), 2.70 (1H, dd, J = 16 , 5Hz), 2.55 (1H, dd, J = 17,8Hz), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.26 (3H, t, J = 7.0Hz)

[0448] 质量(m/e)214(M+1) [0448] mass (m / e) 214 (M + 1)

[0449] 制备12:合成5-氨基-4,4-二氟-戊酸甲酯盐酸盐 [0449] Preparation 12: Synthesis of 5-amino-4,4-difluoro - pentanoic acid methyl ester hydrochloride

[0450] (1)合成3,3-二氟-哌啶-1-羧酸叔-丁酯 [0450] (1) Synthesis of 3,3-difluoro - piperidine-1-carboxylic acid tert - butyl ester

[0451] 400mg(2.0mmol)3-氧代-哌啶-1-羧酸叔-丁酯溶解于二氯甲烷,并冷却至-78℃,然后向其中滴加0.53mL二乙基氨基三氟化硫(DAST,4.0mmol),接着搅拌19小时。 [0451] 400mg (2.0mmol) 3- oxo - piperidine-1-carboxylic acid tert - butyl ester was dissolved in dichloromethane and cooled to -78 deg.] C, and then added dropwise 0.53mL diethylamino-trifluoroethyl sulfur (DAST, 4.0mmol), followed by stirring for 19 hours. 其后,温度升高至室温,并向反应液加入约0.3mL水。 Thereafter, the temperature was raised to room temperature, and the reaction solution was added about 0.3mL water. 浓缩后,残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到0.29g标题化合物,收率64%。 After concentration, the residue was purified by column chromatography (10:1 hexanes: ethyl acetate) to give 0.29g of the title compound in 64% yield.

[0452] 1#H NMR(CDCl3)δ3.61(2H,t,J=11Hz),3.4(2H,m),1.9-2.0(2H,m),1.7-1.8(2H,m),1.45(9H,s) [0452] 1 # H NMR (CDCl3) δ3.61 (2H, t, J = 11Hz), 3.4 (2H, m), 1.9-2.0 (2H, m), 1.7-1.8 (2H, m), 1.45 ( 9H, s)

[0453] 质量(m/e)244(M+Na) [0453] mass (m / e) 244 (M + Na)

[0454] (2)合成5,5-二氟-2-氧代-哌啶-1-羧酸叔-丁酯 [0454] (2) Synthesis of 5,5-difluoro-2-oxo - piperidine-1-carboxylic acid tert - butyl ester

[0455] 0.53g(2.5mmol)甲高碘酸钠(NaIO4)溶解于4mL水,然后向其中加入22mg(0.17mmol)氧化钌(RuO2)。 [0455] 0.53g (2.5mmol) methyl sodium periodate (NaI04) was dissolved in 4mL of water, then added 22mg (0.17mmol) of ruthenium oxide (RuO2). 所得溶液溶解于7mL乙酸乙酯。 The resulting solution was dissolved in 7mL of ethyl acetate. 向该溶液加入上述步骤(1)获得的110mg(0.5mmol)3,3-二氟-哌啶-1-羧酸叔-丁酯,接着室温下搅拌21小时。 110mg (0.5mmol) was added to the above-described step (1) is obtained 3,3-difluoro - piperidine-1-carboxylic acid tert - butyl ester, followed by stirring at room temperature for 21 hours. 搅拌后,反应液以过量乙酸乙酯稀释,并分别用水和NaCl水溶液洗涤一次,用无水硫酸钠干燥,过滤。 After stirring, the reaction solution was diluted with excess ethyl acetate, and washed with water and aqueous NaCl solution once, dried over anhydrous sodium sulfate, and filtered. 减压下蒸馏掉滤液,然后残留物通过柱层析纯化(2∶1己烷∶乙酸乙酯),得到91mg标题化合物,收率78%。 The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography (1 hexanes: ethyl acetate) to give 91mg of the title compound in 78% yield.

[0456] 1H NMR(CDCl3)δ3.97(2H,t,J=13Hz),2.66(2H,t,J=7.0Hz),2.3-2.4(2H,m),1.53(9H,s) [0456] 1H NMR (CDCl3) δ3.97 (2H, t, J = 13Hz), 2.66 (2H, t, J = 7.0Hz), 2.3-2.4 (2H, m), 1.53 (9H, s)

[0457] 质量(m/e)258(M+Na) [0457] mass (m / e) 258 (M + Na)

[0458] (3)合成5-叔-丁氧基羰基氨基-4,4-二氟-戊酸甲酯 [0458] (3) Synthesis of 5-tert - butoxycarbonylamino-4,4-difluoro - pentanoic acid methyl ester

[0459] 将上述步骤(2)获得的91mg(0.39mmol)5,5-二氟-2-氧代-哌啶-1-羧酸叔-丁酯溶解于甲醇,然后向其中加入42mg(0.78mmol)甲醇钠,接着搅拌20分钟。 [0459] The above step (2) 91mg obtained (0.39 mmol) of 5,5-difluoro-2-oxo - piperidine-1-carboxylic acid tert - butyl ester was dissolved in methanol, and thereto was added 42mg (0.78 mmol) of sodium methoxide, followed by stirring for 20 minutes. 浓缩后,反应以过量乙酸乙酯稀释,并分别用1N盐酸水溶液和NaCl水溶液洗涤一次,然后用无水硫酸镁干燥,过滤。 After concentration, the reaction was diluted with excess ethyl acetate, and was washed with 1N aqueous hydrochloric acid and once with aqueous NaCl solution, then dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,残留物通过柱层析纯化(2∶1己烷∶乙酸乙酯),得到73mg标题化合物,收率71%。 The filtrate was distilled off under reduced pressure, the residue was purified by column chromatography (1 hexanes: ethyl acetate) to give 73mg of the title compound in 71% yield.

[0460] 1H NMR(CDCl3)δ4.83(1H,br s),3.69(3H,s),3.4-3.6(2H,m),2.55(2H,t,J=8Hz),2.1-2.3(2H,m),1.44(9H,s) [0460] 1H NMR (CDCl3) δ4.83 (1H, br s), 3.69 (3H, s), 3.4-3.6 (2H, m), 2.55 (2H, t, J = 8Hz), 2.1-2.3 (2H , m), 1.44 (9H, s)

[0461] 质量(m/e)290(M+Na) [0461] mass (m / e) 290 (M + Na)

[0462] (4)合成5-氨基-4,4-二氟-戊酸甲酯盐酸盐 [0462] (4) Synthesis of 5-amino-4,4-difluoro - pentanoic acid methyl ester hydrochloride

[0463] 上述步骤(3)获得的73mg(0.27mmol)5-叔-丁氧基羰基氨基-4,4-二氟-戊酸甲酯与乙酸乙酯/盐酸反应,接着搅拌25分钟。 Obtained [0463] the above step (3) 73mg (0.27mmol) 5- tert - butoxycarbonylamino-4,4-difluoro - pentanoic acid methyl ester / ethyl acetate to react with hydrochloric acid, followed by stirring for 25 minutes. 其后,反应液以二乙基醚浓缩并固化,得到40mg标题化合物,收率88%。 Thereafter, the reaction mixture was concentrated and solidified with diethyl ether to give the title compound 40mg, 88% yield.

[0464] 1H NMR(CD3OD)δ3.68(3H,s),3.48(2H,t,J=15Hz),2.59(2H,t,J=7.5Hz),2.3-2.4(2H,m) [0464] 1H NMR (CD3OD) δ3.68 (3H, s), 3.48 (2H, t, J = 15Hz), 2.59 (2H, t, J = 7.5Hz), 2.3-2.4 (2H, m)

[0465] 质量(m/e)168(M+1) [0465] mass (m / e) 168 (M + 1)

[0466] 制备13:合成3S-叔-丁氧基羰基氨基-4-羟基-丁酸苄酯 [0466] Preparation 13: Synthesis of 3S- tert - butoxycarbonyl-4-hydroxy - butyric acid benzyl ester

[0467] 2S-叔-丁氧基羰基氨基-琥珀酸4-苄酯6.46g(20mmol)溶解于四氢呋喃,然后冷却至0℃。 [0467] 2S- tert - butoxycarbonyl amino - succinic acid 4-benzyl ester 6.46g (20mmol) was dissolved in tetrahydrofuran and then cooled to 0 ℃. 向所得溶液依序滴加1.9mL(20mmol)氯甲酸乙酯和2.79mL三乙胺。 Sequentially added dropwise 1.9mL (20mmol) of ethyl chloroformate 2.79mL of triethylamine and to the resulting solution. 30分钟之后,向其中加入1.5g(40mmol)硼氢化钠,反应液缓慢倾倒至甲醇,接着搅拌1小时。 After 30 minutes, to which was added 1.5g (40mmol) of sodium borohydride, the reaction solution was slowly poured into methanol, followed by stirring for 1 hour. 其后,反应液以过量乙酸乙酯稀释,并分别用1N HCl水溶液和NaCl水溶液洗涤一次,用无水硫酸镁干燥,并过滤。 Thereafter, the reaction solution was diluted with excess ethyl acetate, and was washed with aqueous 1N HCl and once with aqueous NaCl solution, dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,然后残留物通过柱层析纯化(4∶1己烷∶乙酸乙酯),得到4.44g标题化合物,收率72%。 The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography (4:1 hexanes: ethyl acetate) to give the title compound 4.44g, 72% yield.

[0468] 1H NMR(CDCl3)δ7.3-7.4(5H,m),5.21(1H,d,J=8Hz),5.12(2H,s),4.0(1H,m),3.69(2H,d,J=5Hz),2.67(2H,d,J=5.5Hz),1.42(9H,s) [0468] 1H NMR (CDCl3) δ7.3-7.4 (5H, m), 5.21 (1H, d, J = 8Hz), 5.12 (2H, s), 4.0 (1H, m), 3.69 (2H, d, J = 5Hz), 2.67 (2H, d, J = 5.5Hz), 1.42 (9H, s)

[0469] 质量(m/e)310(M+1) [0469] mass (m / e) 310 (M + 1)

[0470] 制备14:合成3S-叔-丁氧基羰基氨基-4-氧代-丁酸苄酯 [0470] Preparation 14: Synthesis of 3S- tert - butoxycarbonylamino-4-oxo - butyric acid benzyl ester

[0471] 将0.31g(1.0mmol)3S-叔-丁氧基羰基氨基-4-羟基-丁酸苄酯溶解于制备13获得的二氯甲烷,然后向其中加入6mL Dess-Martin(~0.3M),接着搅拌4小时。 [0471] A 0.31g (1.0mmol) 3S- tert - butoxycarbonyl-4-hydroxy - butyric acid benzyl ester was dissolved in dichloromethane obtained in Preparation 13, and then thereto was added 6mL Dess-Martin (~ 0.3M ), followed by stirring for 4 hours. 浓缩后,残留物通过柱层析纯化(2∶1己烷∶乙酸乙酯),得到0.23g标题化合物,收率75%。 After concentration, the residue was purified by column chromatography (1 hexanes: ethyl acetate) to give 0.23g of the title compound in 75% yield.

[0472] 1H NMR(CDCl3)δ9.64(1H,s),7.3-7.4(5H,m),5.6(1H,d,J=7.5Hz),5.12(2H,s),4.35(1H,m),3.05(1H,dd,J=15.0,5.0Hz),2.88(1H,dd,J=15.0,5.0Hz),1.44(9H,s) [0472] 1H NMR (CDCl3) δ9.64 (1H, s), 7.3-7.4 (5H, m), 5.6 (1H, d, J = 7.5Hz), 5.12 (2H, s), 4.35 (1H, m ), 3.05 (1H, dd, J = 15.0,5.0Hz), 2.88 (1H, dd, J = 15.0,5.0Hz), 1.44 (9H, s)

[0473] 质量(m/e)308(M+1) [0473] mass (m / e) 308 (M + 1)

[0474] 制备15:合成3S-叔-丁氧基羰基氨基-4-(2-羟基-乙基氨基)-丁酸苄酯 [0474] Preparation 15: Synthesis of 3S- tert - butoxycarbonylamino-4- (2-hydroxy - ethylamino) - butyric acid benzyl ester

[0475] 制备14获得的0.68g(2.2mmol)3S-叔-丁氧基羰基氨基-4-氧代-丁酸苄酯溶解于二氯乙烷,冷却至0℃,然后向其中加入2-氨基乙醇(1301,2.2mmol),接着搅拌约30分钟。 [0475] Preparation 14 0.68g (2.2mmol) 3S- obtained tert - butoxycarbonylamino-4-oxo - butyric acid benzyl ester was dissolved in dichloroethane, was cooled to 0 deg.] C, then added 2- aminoethanol (1301,2.2mmol), followed by stirring for about 30 minutes. 其后,向其中加入三乙酸基硼氢化钠1.4g(6.6mmol),接着搅拌约1又1/6小时。 Thereafter, thereto was added sodium triacetoxy boron hydride 1.4g (6.6mmol), followed by stirring for about 1 and 1/6 hour. 所得溶液以二氯甲烷稀释,并用饱和碳酸氢钠水溶液洗涤,然后用无水硫酸镁干燥,并过滤。 The resulting solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,残留物通过柱层析纯化(1∶1己烷∶乙酸乙酯→10∶1CH2Cl2∶MeOH),得到0.14g标题化合物,收率18%。 The filtrate was distilled off under reduced pressure, the residue was purified by column chromatography (1 hexanes: ethyl acetate → 10:1CH2Cl2:MeOH), to give 0.14g of the title compound in a yield of 18%.

[0476] 1H NMR(CDCl3)δ7.3-7.4(5H,m),5.8-6.1(1H,m),5.12(2H,s),4.15-4.35(1H,m),3.7-3.8(2H,m),2.9-3.15(4H,m),2.6-2.8(2H,m),1.42(9H,s) [0476] 1H NMR (CDCl3) δ7.3-7.4 (5H, m), 5.8-6.1 (1H, m), 5.12 (2H, s), 4.15-4.35 (1H, m), 3.7-3.8 (2H, m), 2.9-3.15 (4H, m), 2.6-2.8 (2H, m), 1.42 (9H, s)

[0477] 质量(m/e)353(M+1) [0477] mass (m / e) 353 (M + 1)

[0478] 制备16:合成3S-叔-丁氧基羰基氨基-4-(2-氧代-噁唑烷-3-基)-丁酸苄酯 [0478] Preparation 16: Synthesis of 3S- tert - butoxycarbonylamino-4- (2-oxo - oxazolidin-3-yl) - butyric acid benzyl ester

[0479] 制备15获得的140mg(0.4mmol)3S-叔-丁氧基羰基氨基-4-(2-羟基-乙基氨基)-丁酸苄酯溶解于二氯甲烷,然后冷却至0℃,向其中加入2801(1.6mmol)N,N-二异丙基乙胺和49mg(0.4mmol)二甲基氨基吡啶,接着加入0.4g(0.6mmol)光气(20%甲苯),搅拌2小时40分钟。 [0479] Preparation 15 140mg (0.4mmol) 3S- obtained tert - butoxycarbonylamino-4- (2-hydroxy - ethylamino) - butyric acid benzyl ester was dissolved in dichloromethane and then cooled to 0 deg.] C, to this was added 2801 (1.6mmol) N, N- diisopropylethylamine and 49 mg (0.4 mmol) of dimethylaminopyridine, followed by addition of 0.4g (0.6mmol) of phosgene (20% in toluene), stirred for 2 hours 40 minute. 其后,所得溶液以二氯甲烷稀释,并用NaCl水溶液洗涤,然后用无水硫酸镁干燥和过滤。 Thereafter, the resulting solution was diluted with dichloromethane and washed with aqueous NaCl, then dried over anhydrous magnesium sulfate and filtered. 减压下蒸馏掉滤液,残留物通过柱层析纯化(1∶1己烷∶乙酸乙酯),得到30mg标题化合物,收率20%。 The filtrate was distilled off under reduced pressure, the residue was purified by column chromatography (1 hexanes: ethyl acetate) to give 30mg of the title compound in 20% yield.

[0480] 1H NMR(CDCl3)δ7.3-7.4(5H,m),5.12(2H,s),5.1(1H,m),4.3(2H,m),4.2(1H,m),3.76(1H,m),3.5(2H,m),3.22(1H,m),2.63(1H,dd,J=16,5.5Hz),2.58(1H,dd,J=16,6.5Hz),1.41(9H,s) [0480] 1H NMR (CDCl3) δ7.3-7.4 (5H, m), 5.12 (2H, s), 5.1 (1H, m), 4.3 (2H, m), 4.2 (1H, m), 3.76 (1H , m), 3.5 (2H, m), 3.22 (1H, m), 2.63 (1H, dd, J = 16,5.5Hz), 2.58 (1H, dd, J = 16,6.5Hz), 1.41 (9H, s)

[0481] 质量(m/e)379(M+1) [0481] mass (m / e) 379 (M + 1)

[0482] 制备17:合成[3-氧代-1-(2-氧代-噁唑烷-3-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0482] Preparation 17: Synthesis of [3-oxo-1- (2-oxo - oxazolidin-3-yl) -3- (3-trifluoromethyl-5,6-dihydro -8H - [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0483] 制备16获得的30mg(0.079mmol)3S-叔-丁氧基羰基氨基-4-(2-氧代-噁唑烷-3-基)-丁酸苄酯溶解于甲醇,然后向其中加入3mg钯/carcol(Pd/C),接着在氢气氛下搅拌3小时40分钟。 30mg [0483] obtained in Preparation 16 (0.079mmol) 3S- tert - butoxycarbonylamino-4- (2-oxo - oxazolidin-3-yl) - butyric acid benzyl ester was dissolved in methanol, to which was then palladium was added 3mg / carcol (Pd / C), followed by stirring under a hydrogen atmosphere for 3 hours and 40 minutes. 反应完成后,反应液经Cellite过滤,然后以甲醇洗涤,浓缩。 After completion of the reaction, the reaction solution was filtered by Cellite, and then washed with methanol, and concentrated. 向该反应中,立即加入15mg(0.079mmol)3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪,然后溶解于二氯甲烷。 To the reaction was immediately added 15mg (0.079mmol) 3- trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazine, then dissolved in dichloromethane. 反应冷却至0℃,然后加入13mg(0.095mmol)HOBT,之后搅拌10分钟,向其中加入23mg(0.12mmol)EDC。 The reaction was cooled to 0 deg.] C, followed by addition of 13mg (0.095mmol) HOBT, stirred for 10 minutes, to which was added 23mg (0.12mmol) EDC. 去除冰浴之后,反应液搅拌约17小时,然后浓缩残留物通过prep-TCL(10∶1CH2Cl2∶MeOH)纯化,得到21mg标题化合物,总收率57%。 After the ice bath was removed and the reaction was stirred for about 17 hours, then the concentrated residue was purified by prep-TCL (10:1CH2Cl2:MeOH), to give 21mg of the title compound in a total yield of 57%.

[0484] 1H NMR(CDCl3)δ5.6-5.8(1H,m),4.9-5.1(2H,m),4.0-4.4(6H,m),3.6-3.8(2H,m),3.3-3.5(2H,m),2.6-2.9(2H,m),1.39(9H,s) [0484] 1H NMR (CDCl3) δ5.6-5.8 (1H, m), 4.9-5.1 (2H, m), 4.0-4.4 (6H, m), 3.6-3.8 (2H, m), 3.3-3.5 ( 2H, m), 2.6-2.9 (2H, m), 1.39 (9H, s)

[0485] 质量(m/e)463(M+1) [0485] mass (m / e) 463 (M + 1)

[0486] 实施例1:合成3-[2S-氨基-4-氧代-4-(3三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-噁唑烷-2-酮 [0486] Example 1: Synthesis of 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4 , 3-a] pyrazin-7-yl) - butyl] - oxazolidin-2-one

[0487] [0487]

[0488] 制备17获得的21mg(0.045mmol)[3-氧代-1-(2-氧代-噁唑烷-3-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯溶解于乙酸乙酯/盐酸,接着搅拌约17小时,然后溶液浓缩,得到白色固体。 21mg [0488] obtained in Preparation 17 (0.045 mmol) [3- oxo-1- (2-oxo - oxazolidin-3-yl) -3- (3-trifluoromethyl-5,6 - dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester was dissolved in ethyl acetate / hydrochloric acid , followed by stirring for about 17 hours, then the solution was concentrated to give a white solid. 其后,固体以二乙基醚洗涤,并干燥得到15mg标题化合物,收率91%。 Thereafter, the solid was washed with diethyl ether, and dried to give 15mg of the title compound in 91% yield.

[0489] 1H NMR(CD3OD)δ5.06(2H,s),4.4(3H,m),4.26(1H,m),4.05-4.15(2H,m),3.9(1H,m),3.5-3.8(4H,m),3.0-3.1(1H,m),2.85-2.95(1H,m), [0489] 1H NMR (CD3OD) δ5.06 (2H, s), 4.4 (3H, m), 4.26 (1H, m), 4.05-4.15 (2H, m), 3.9 (1H, m), 3.5-3.8 (4H, m), 3.0-3.1 (1H, m), 2.85-2.95 (1H, m),

[0490] 质量(m/e)363(M+1) [0490] mass (m / e) 363 (M + 1)

[0491] 制备18:合成3S-叔-丁氧基羰基氨基-4-(2-羟基-丙基氨基)-丁酸苄酯 [0491] Preparation 18: Synthesis of 3S- tert - butoxycarbonylamino-4- (2-hydroxy - propyl-amino) - butyric acid benzyl ester

[0492] 制备14获得的0.68g(2.2mmol)3S-叔-丁氧基羰基氨基-4-氧代-丁酸苄酯溶解于二氯乙烷,然后冷却至0℃,之后向其中加入2-氨基乙醇(1701,2.2mmol),接着搅拌30分钟。 [0492] obtained in Preparation 14 0.68g (2.2mmol) 3S- tert - butoxycarbonylamino-4-oxo - butyric acid benzyl ester was dissolved in dichloroethane and then cooled to 0 deg.] C, and thereto was added 2 - aminoethanol (1701,2.2mmol), followed by stirring for 30 minutes. 其后,向溶液加入1.4g(6.6mmol)三乙酸基硼氢化钠,接着搅拌约1小时10分钟。 Thereafter, triacetoxy sodium boron hydride 1.4g (6.6mmol) added to the solution, followed by stirring for about 1 hour and 10 minutes. 其后,该溶液以二氯甲烷稀释,然后用饱和碳酸氢钠水溶液洗涤,用无水硫酸镁干燥,并过滤。 Thereafter, the solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,残留物通过柱层析纯化(1∶1己烷∶乙酸乙酯→10∶1CH2Cl2∶MeOH),得到0.36g标题化合物,收率45%。 The filtrate was distilled off under reduced pressure, the residue was purified by column chromatography (1 hexanes: ethyl acetate → 10:1CH2Cl2:MeOH), to give 0.36g of the title compound in 45% yield.

[0493] 1H NMR(CDCl3)δ7.3-7.4(5H,m),5.8-6.0(1H,m),5.10(2H,m),3.9-4.0(1H,m),2.5-3.1(6H,m),1.40(9H,s),1.15(3H,d,J=7Hz) [0493] 1H NMR (CDCl3) δ7.3-7.4 (5H, m), 5.8-6.0 (1H, m), 5.10 (2H, m), 3.9-4.0 (1H, m), 2.5-3.1 (6H, m), 1.40 (9H, s), 1.15 (3H, d, J = 7Hz)

[0494] 质量(m/e)367(M+1) [0494] mass (m / e) 367 (M + 1)

[0495] 制备19:合成3S-叔-丁氧基羰基氨基-4-(5-甲基-2-氧代-噁唑烷-3-基)-丁酸苄酯 [0495] Preparation 19: Synthesis of 3S- tert - butoxycarbonylamino-4- (5-methyl-2-oxo - oxazolidin-3-yl) - butyric acid benzyl ester

[0496] 制备18获得的360mg(0.98mmol)3S-叔-丁氧基羰基氨基-4-(2-羟基-丙基氨基)-丁酸苄酯溶解于二氯甲烷,然后冷却至0℃,之后向其中加入120mg(0.98mmol)N,N-二异丙基乙胺和6801(3.92mmol)二甲基氨基吡啶,接着加入1.0g(1.5mmol)光气(20%甲苯),然后搅拌2小时40分钟。 360mg [0496] obtained in Preparation 18 (0.98mmol) 3S- tert - butoxycarbonylamino-4- (2-hydroxy - propyl-amino) - butyric acid benzyl ester was dissolved in dichloromethane and then cooled to 0 deg.] C, after added thereto 120mg (0.98mmol) N, N- diisopropylethylamine and 6801 (3.92mmol) of dimethylaminopyridine, followed by addition of 1.0g (1.5mmol) of phosgene (20% in toluene), and then stirred for 2 hours and 40 minutes. 反应液以二氯甲烷稀释,并用NaCl水溶液洗涤,然后用无水硫酸镁干燥和过滤。 The reaction solution was diluted with dichloromethane and washed with aqueous NaCl, then dried over anhydrous magnesium sulfate and filtered. 减压下蒸馏掉滤液,残留物通过柱层析纯化(1∶1己烷∶乙酸乙酯),得到120mg标题化合物,收率31%。 The filtrate was distilled off under reduced pressure, the residue was purified by column chromatography (1 hexanes: ethyl acetate) to give 120mg of the title compound in 31% yield.

[0497] 1H NMR(CDCl3)δ7.3-7.4(5H,m),5.10(2H,s),5.10(1H,m),4.55-4.65(1H,m),4.1-4.2(1H,m),3.0-3.8(3H,m),2.5-2.8(2H,m),1.41(12H,m) [0497] 1H NMR (CDCl3) δ7.3-7.4 (5H, m), 5.10 (2H, s), 5.10 (1H, m), 4.55-4.65 (1H, m), 4.1-4.2 (1H, m) , 3.0-3.8 (3H, m), 2.5-2.8 (2H, m), 1.41 (12H, m)

[0498] 质量(m/e)393(M+1) [0498] mass (m / e) 393 (M + 1)

[0499] 制备20:合成[1-(5-甲基-2-氧代-噁唑烷-3-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0499] Preparation 20: Synthesis of [1- (5-methyl-2-oxo - oxazolidin-3-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6 - dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0500] 制备19获得的3S-叔-丁氧基羰基氨基-4-(5-甲基-2-氧代-噁唑烷-3-基)-丁酸苄酯120mg(0.31mmol)溶解于甲醇,然后向其中加入12mg钯/carcol(Pd/C),接着在氢气氛下搅拌3小时40分钟。 [0500] 3S- obtained in Preparation 19 tert - butoxycarbonylamino-4- (5-methyl-2-oxo - oxazolidin-3-yl) - butyric acid benzyl ester 120mg (0.31mmol) was dissolved in methanol, then added 12mg Pd / carcol (Pd / C), followed by stirring under a hydrogen atmosphere for 3 hours and 40 minutes. 反应完成后,反应液经Cellite过滤,然后以甲醇洗涤,接着浓缩。 After completion of the reaction, the reaction solution was filtered by Cellite, and then washed with methanol, then concentrated. 立即向其中加入9mg(0.31mmol)胺,所得溶液溶解于二氯甲烷。 Now added 9mg (0.31mmol) amine added thereto, the resulting solution was dissolved in dichloromethane. 反应冷却至0℃,然后其中加入50mg(0.37mmol)HOBT。 The reaction was cooled to 0 ℃, then added 50mg (0.37mmol) HOBT. 搅拌10分钟之后,再加入88mg(0.47mmol)EDC。 After stirring for 10 minutes, then added 88mg (0.47mmol) EDC. 去除冰浴之后,反应液搅拌约17小时,浓缩的残留物通过prep-TLC纯化(10∶1CH2Cl2∶MeOH)纯化,得到88mg标题化合物,总收率60%。 After the ice bath was removed and the reaction was stirred for about 17 hours, the concentrated residue was purified by TLC prep-purified (10:1CH2Cl2:MeOH), to give 88mg of the title compound, total yield 60%.

[0501] 1H NMR(CDCl3)δ5.6-5.9(1H,m),4.9-5.1(2H,m),4.6-4.8(1H,m),3.9-4.3(5H,m),3.6-3.8(1H,m),3.1-3.5(3H,m),2.5-2.9(2H,m),1.40(12H,m) [0501] 1H NMR (CDCl3) δ5.6-5.9 (1H, m), 4.9-5.1 (2H, m), 4.6-4.8 (1H, m), 3.9-4.3 (5H, m), 3.6-3.8 ( 1H, m), 3.1-3.5 (3H, m), 2.5-2.9 (2H, m), 1.40 (12H, m)

[0502] 质量(m/e)477(M+1) [0502] mass (m / e) 477 (M + 1)

[0503] 实施例2:合成3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5-甲基-噁唑烷-2-酮 [0503] Example 2: Synthesis of 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -5-methyl - oxazolidin-2-one

[0504] [0504]

[0505] 制备20获得的88mg(0.045mmol)[1-(5-甲基-2-氧代-噁唑烷-3-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯溶解于乙酸乙酯/盐酸。 [0505] 88mg (0.045mmol) obtained in Preparation 20 [1- (5-methyl-2-oxo - oxazolidin-3-ylmethyl) -3-oxo-3- (3-trifluoromethylsulfonyl -5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester was dissolved in ethyl acetate / hydrochloric acid. 搅拌约30分钟之后,反应液浓缩,得到白色固体。 After stirring for about 30 minutes, the reaction mixture was concentrated to give a white solid. 其后,固体以二乙基醚洗涤,并干燥,得到42mg标题化合物,收率60%。 Thereafter, the solid was washed with diethyl ether, and dried to give 42mg of the title compound in 60% yield.

[0506] 1H NMR(CD30D)δ5.1-5.2(2H,m),4.7-4.8(1H,m),4.45(1H,m),4.3(1H,m),4.0-4.2(3H,m),3.8-3.9(2H,m),3.4-3.7(2H,m),2.9-3.1(2H,m),1.41(3H,m) [0506] 1H NMR (CD30D) δ5.1-5.2 (2H, m), 4.7-4.8 (1H, m), 4.45 (1H, m), 4.3 (1H, m), 4.0-4.2 (3H, m) , 3.8-3.9 (2H, m), 3.4-3.7 (2H, m), 2.9-3.1 (2H, m), 1.41 (3H, m)

[0507] 质量(m/e)377(M+1) [0507] mass (m / e) 377 (M + 1)

[0508] 制备21:合成3S-叔-丁氧基羰基氨基-4-(叔-丁基-二甲基-硅烷基氧基)-丁酸苄酯 [0508] Preparation 21: Synthesis of 3S- tert - butoxycarbonylamino-4- (tert - butyl - dimethyl - silanyloxy) - butyric acid benzyl ester

[0509] 将制备13获得的4.0g(12.9mmol)3S-叔-丁氧基羰基氨基-4-羟基-丁酸苄酯溶解于二甲基甲酰胺,然后向其中加入2.34g(15.5mmol)咪唑和2.34g(32.3mmol)叔-丁基二甲基甲硅烷基氯化物,接着搅拌约2小时。 [0509] Preparation 13 The obtained 4.0g (12.9mmol) 3S- tert - butoxycarbonyl-4-hydroxy - butyric acid benzyl ester was dissolved in dimethylformamide, then added 2.34g (15.5mmol) imidazole and 2.34g (32.3mmol) t - butyldimethyl silyl chloride, followed by stirring for about 2 hours. 其后,溶液以过量乙酸乙酯稀释,并分别用水和NaCl水溶液洗涤一次,然后用无水硫酸镁干燥和过滤。 Thereafter, the solution was diluted with excess ethyl acetate, and washed with water and aqueous NaCl solution once, then dried over anhydrous magnesium sulfate and filtered. 减压下蒸馏掉滤液,残留物通过柱层析纯化(5∶1己烷∶乙酸乙酯),得到4.0g标题化合物,收率73%。 The filtrate was distilled off under reduced pressure, the residue was purified by column chromatography (5:1 hexanes: ethyl acetate) to give 4.0g of the title compound in 73% yield.

[0510] 1EH NMR(CDCl3)δ7.3-7.4(5H,m),5.21(1H,d,J=8Hz),5.08(1H,m),4.0-4.1(1H,m),3.6-3.7(2H,m),2.6-2.7(2H,m),1.42(9H,s),0.86(9H,s),0.01(6H,s) [0510] 1EH NMR (CDCl3) δ7.3-7.4 (5H, m), 5.21 (1H, d, J = 8Hz), 5.08 (1H, m), 4.0-4.1 (1H, m), 3.6-3.7 ( 2H, m), 2.6-2.7 (2H, m), 1.42 (9H, s), 0.86 (9H, s), 0.01 (6H, s)

[0511] 质量(m/e)424(M+1) [0511] mass (m / e) 424 (M + 1)

[0512] 制备22.合成[1-(叔-丁基-二甲基-硅烷基氧基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基)-1S-氨基甲酸叔-丁酯 [0512] Preparation 22. Synthesis of [1- (tert - butyl - dimethyl - silanyloxymethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro - 8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl) amino-1S-tert - butyl ester

[0513] (1)合成3S-叔-丁氧基羰基氨基-4-(叔-丁基-二甲基-硅烷基氧基)-丁酸 [0513] (1) Synthesis of 3S- tert - butoxycarbonylamino-4- (tert - butyl - dimethyl - silanyloxy) - butanoic acid

[0514] 将制备21获得的1.0g(2.36mmol)3S-叔-丁氧基羰基氨基-4-(叔-丁基-二甲基-硅烷基氧基)-丁酸苄酯溶解于甲醇,然后向其中加入120mg钯/carcol(Pd/C),接着在氢气氛下搅拌3小时25分钟。 [0514] The preparation 21 1.0g (2.36mmol) 3S- obtained tert - butoxycarbonylamino-4- (tert - butyl - dimethyl - silanyloxy) - butyric acid benzyl ester was dissolved in methanol, was then added 120mg of palladium / carcol (Pd / C), followed by stirring under a hydrogen atmosphere for 3 hours and 25 minutes. 反应完成之后,反应液经Cellite过滤,用甲醇洗涤,然后浓缩。 After completion of the reaction, the reaction solution was filtered through Cellite, washed with methanol, and then concentrated.

[0515] 1H NMR(CDCl3)δ5.10(1H,m),4.02(1H,m),3.6-3.7(2H,m),2.61(2H,m),1.43(9H,s),0.88(9H,s),0.04(6H,s) [0515] 1H NMR (CDCl3) δ5.10 (1H, m), 4.02 (1H, m), 3.6-3.7 (2H, m), 2.61 (2H, m), 1.43 (9H, s), 0.88 (9H , s), 0.04 (6H, s)

[0516] 质量(m/e)356(M+Na) [0516] mass (m / e) 356 (M + Na)

[0517] (2)合成[1-(叔-丁基-二甲基-硅烷基氧基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0517] (2) Synthesis of [1- (tert - butyl - dimethyl - silanyloxymethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro - 8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0518] 获自步骤(1)的333mg(1mmol)3S-叔-丁氧基羰基氨基-4-(叔-丁基-二甲基-硅烷基氧基)-丁酸加入192mg(1mmol)3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪,并将所得混合物溶解于二氯甲烷。 [0518] obtained from step (1) of 333mg (1mmol) 3S- tert - butoxycarbonylamino-4- (tert - butyl - dimethyl - silanyloxy) - butanoic acid was added 192mg (1mmol) 3 - trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazine, and the resulting mixture was dissolved in dichloromethane. 反应液冷却至0℃,加入162mg(1.2mmol)HOBT,接着搅拌10分钟,再加入288mg(1.5mmol)EDC。 The reaction solution was cooled to 0 deg.] C, was added 162mg (1.2mmol) HOBT, followed by stirring for 10 minutes, was added 288mg (1.5mmol) EDC. 取出冰浴之后,反应液搅拌约13小时,然后通过浓缩获得的残留物以柱层析纯化(1∶1己烷∶乙酸乙酯),得到0.27g标题化合物,收率53%。 After removing the ice bath, the reaction solution was stirred for about 13 hours, and then the residue obtained by concentration was purified by column chromatography to (1 hexanes: ethyl acetate) to give 0.27g of the title compound in 53% yield.

[0519] 1H NMR(CDCl3)δ5.1-5.3(1H,m),4.9-5.1(2H,m),3.9-4.3(4H,m),3.7-3.8(2H,m),2.6-2.9(2H,m),1.40(9H,s),0.87(9H,s),0.03(6H,s) [0519] 1H NMR (CDCl3) δ5.1-5.3 (1H, m), 4.9-5.1 (2H, m), 3.9-4.3 (4H, m), 3.7-3.8 (2H, m), 2.6-2.9 ( 2H, m), 1.40 (9H, s), 0.87 (9H, s), 0.03 (6H, s)

[0520] 质量(m/e)508(M+1) [0520] mass (m / e) 508 (M + 1)

[0521] 制备23:合成[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0521] Preparation 23: Synthesis of [1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4, 3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0522] (1)合成[1-羟基甲基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0522] (1) Synthesis of [1-hydroxy methyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4 , 3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0523] 将制备22获得的2.3g(4.53mmol)[1-(叔-丁基-二甲基-硅烷基氧基甲基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基)-1S-氨基甲酸叔-丁酯溶解于四氢呋喃,然后向其中滴加9mL氟化四丁铵(1MTHF溶液),接着搅拌约12分钟。 [0523] Preparation 22 The obtained 2.3g (4.53mmol) [1- (tert - butyl - dimethyl - silanyloxymethyl 3-oxo-3- (3-methyl-5 1,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl) amino-1S-tert - butyl ester was dissolved in tetrahydrofuran, and then 9mL added dropwise tetrabutylammonium fluoride (1M THF solution), followed by stirring for about 12 minutes. 溶液以过量乙酸乙酯稀释之后,稀释溶液分别用水和NaCl水溶液洗涤一次,用无水硫酸镁干燥并过滤。 After excess solution was diluted with ethyl acetate, the solution was diluted with water and once with aqueous NaCl solution, dried over anhydrous magnesium sulfate and filtered. 减压下蒸馏掉滤液,残留物然后通过柱层析纯化(15∶1CH2Cl2∶MeOH),得到1.78g[1-羟基甲基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯,收率99%。 The filtrate residue was then purified by column chromatography (15:1CH2Cl2:MeOH), to give 1.78g [1- hydroxy-3-oxo-3- (3-methyl-5 was distilled under reduced pressure off, 1,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester, 99% yield.

[0524] 1H NMR(CDCl3)δ5.3-5.5(1H,m),5.0-5.2(2H,m),3.9-4.3(4H,m),3.6-3.8(2H,m),2.7-3.0(2H,m),1.41(9H,s) [0524] 1H NMR (CDCl3) δ5.3-5.5 (1H, m), 5.0-5.2 (2H, m), 3.9-4.3 (4H, m), 3.6-3.8 (2H, m), 2.7-3.0 ( 2H, m), 1.41 (9H, s)

[0525] 质量(m/e)394(M+1) [0525] mass (m / e) 394 (M + 1)

[0526] (2)合成[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0526] (2) Synthesis of [1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4, 3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0527] 将获自步骤(1)的500mg(1.27mmol)[1-羟基甲基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯溶解于二氯甲烷,然后向其中加入10mL Dess-Martin(~0.3M),接着搅拌2小时40分钟。 [0527] obtained from step (1) of 500mg (1.27mmol) [1- hydroxymethyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1, 2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester was dissolved in dichloromethane, and then thereto was added 10mL Dess-Martin (~ 0.3M), followed by stirring for 2 hours 40 minutes. 浓缩之后,残留物通过柱层析纯化(1∶2己烷∶乙酸乙酯),得到0.33g标题化合物,收率66%。 After concentration, the residue was purified by column chromatography (1:2 hexanes: ethyl acetate) to give 0.33g of the title compound, yield 66%.

[0528] 1H NMR(CDCl3)δ9.67(1H,s),5.7-5.9(1H,m),4.9-5.1(2H,m),3.9-4.5(5H,m),3.1-3.2(1H,m),2.9-3.0(1H,m),1.42(9H,s) [0528] 1H NMR (CDCl3) δ9.67 (1H, s), 5.7-5.9 (1H, m), 4.9-5.1 (2H, m), 3.9-4.5 (5H, m), 3.1-3.2 (1H, m), 2.9-3.0 (1H, m), 1.42 (9H, s)

[0529] 质量(m/e)392(M+1) [0529] mass (m / e) 392 (M + 1)

[0530] 制备24:合成[3-氧代-1-(2-氧代-哌啶-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0530] Preparation 24: Synthesis of [3-oxo-1- (2-oxo - piperidin-1-yl) -3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0531] 77mg(0.2mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯加入33mg(0.2mmol)5-氨基-戊酸甲酯盐酸盐,再溶解于二氯乙烷,接着搅拌30分钟。 [0531] 77mg (0.2mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4 , 3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester was added 33mg (0.2mmol) 5- amino - pentanoic acid methyl ester hydrochloride, redissolved in dichloroethane , followed by stirring for 30 minutes. 向溶液加入83mg(0.4mmol)三乙酸基硼氢化钠,接着搅拌约1小时40分钟。 To the solution was added 83mg (0.4mmol) of sodium borohydride triacetate group, followed by stirring for about 1 hour and 40 minutes. 所得溶液加热至80℃,约7小时,并浓缩,然后残留物通过prep-TCL纯化(10∶1CH2Cl2∶MeOH),得到约20g标题化合物,总收率21%。 The resulting solution was heated to 80 ℃, about 7 hours, and concentrated, then the residue was purified by prep-TCL (10:1CH2Cl2:MeOH) to afford about 20g of the title compound in a total yield of 21%.

[0532] 1H NMR(CD3OD)δ6.5(1H,m),4.9-5.1(2H,m),4.0-4.4(5H,m),3.35-3.5(3H,m),2.6-2.8(2H,m),2.28(2H,t,J=6.0Hz),1.7-1.8(4H,m),1.36(9H,s) [0532] 1H NMR (CD3OD) δ6.5 (1H, m), 4.9-5.1 (2H, m), 4.0-4.4 (5H, m), 3.35-3.5 (3H, m), 2.6-2.8 (2H, m), 2.28 (2H, t, J = 6.0Hz), 1.7-1.8 (4H, m), 1.36 (9H, s)

[0533] 质量(m/e)475(M+1) [0533] mass (m / e) 475 (M + 1)

[0534] 实施例3:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-哌啶-2-酮 [0534] Example 3: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] - piperidin-2-one

[0535] [0535]

[0536] 将制备24获得的88mg(0.045mmol)[3-氧代-1-(2-氧代-哌啶-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯溶解于乙酸乙酯/盐酸,接着搅拌约30分钟,然后浓缩。 [0536] The 88mg (0.045mmol) [3- oxo-1 obtained in Preparation 24 (2-oxo - piperidin-1-yl) -3- (3-trifluoromethyl-5,6 - dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester was dissolved in ethyl acetate / hydrochloric acid , followed by stirring for about 30 minutes and then concentrated. 残留物通过prep-TLC纯化(10∶1CH2Cl2∶MeOH),得到约10.4mg标题化合物,收率66%。 The residue was purified by prep-TLC (10:1CH2Cl2:MeOH) to afford the title compound of about 10.4mg, yield 66%.

[0537] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.6(1H,br),4.0-4.4(4H,m),3.8-3.9(2H,m),3.35-3.5(2H,m),2.8-3.0(2H,m),2.0-2.4(2H,m),1.8-1.9(4H,m), [0537] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.6 (1H, br), 4.0-4.4 (4H, m), 3.8-3.9 (2H, m), 3.35-3.5 (2H, m), 2.8-3.0 (2H, m), 2.0-2.4 (2H, m), 1.8-1.9 (4H, m),

[0538] 质量(m/e)375(M+1) [0538] mass (m / e) 375 (M + 1)

[0539] 制备25:合成[1-(4-甲基-2-氧代-吡咯烷-1-基甲基)-3-氢代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0539] Preparation 25: Synthesis of [1- (4-methyl-2-oxo - pyrrolidin-l-ylmethyl) -3-hydrogen-3- (3-trifluoromethyl-5,6 dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0540] 以制备24的相同方式,将制备23获得的50mg(0.13mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与21mg(0.13mmol)4-氨基-3-甲基丁酸甲酯盐酸盐(制备2的产物)mmol反应,得到18mg标题化合物,收率30%。 [0540] In the same manner as in Preparation 24, prepared 23 50mg (0.13mmol) obtained in [1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 21mg (0.13mmol) 4- amino-3- butyric acid methyl ester hydrochloride (the product of preparation 2) mmol to give the title compound 18mg, 30% yield.

[0541] 1H NMR(CDCl3)δ5.7-6.0(1H,m),4.8-5.1(2H,m),3.9-4.4(5H,m),3.3-3.7(3H,m),3.0-3.1(1H,m),2.3-2.9(4H,m),1.9-2.0(1H,m),1.40(9H,s),1.09(3H,d,J=5Hz) [0541] 1H NMR (CDCl3) δ5.7-6.0 (1H, m), 4.8-5.1 (2H, m), 3.9-4.4 (5H, m), 3.3-3.7 (3H, m), 3.0-3.1 ( 1H, m), 2.3-2.9 (4H, m), 1.9-2.0 (1H, m), 1.40 (9H, s), 1.09 (3H, d, J = 5Hz)

[0542] 质量(m/e)475(M+1) [0542] mass (m / e) 475 (M + 1)

[0543] 实施例4:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-吡咯烷-2-酮 [0543] Example 4: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -4-methyl - pyrrolidin-2-one

[0544] [0544]

[0545] 以实施例3的相同方式,将制备25获得的18mg[1-(4-甲基-2-氧代-吡咯烷-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到5.8mg标题化合物,收率37%。 [0545] In the same manner as Example 3, prepared 25 obtained 18mg [1- (4- methyl-2-oxo - pyrrolidin-l-ylmethyl) -3-oxo-3- (3 - trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] -carbamic acid tert-1S-- butyl ester ethyl acetate / reaction with hydrochloric acid, to give 5.8mg of the title compound in 37% yield.

[0546] 1H NMR(CD30D)δ4.9-5.1(2H,m),4.0-4.3(4H,m),3.3-3.7(4H,m),3.0-3.1(1H,m),2.4-2.8(4H,m),1.9-2.0(1H,m),1.1(3H,m), [0546] 1H NMR (CD30D) δ4.9-5.1 (2H, m), 4.0-4.3 (4H, m), 3.3-3.7 (4H, m), 3.0-3.1 (1H, m), 2.4-2.8 ( 4H, m), 1.9-2.0 (1H, m), 1.1 (3H, m),

[0547] 质量(m/e)375(M+1) [0547] mass (m / e) 375 (M + 1)

[0548] 制备26:合成[1-(3-氟-2-氧代-吡咯烷-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0548] Preparation 26: Synthesis of [1- (3-fluoro-2-oxo - pyrrolidin-l-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6- hydrogen -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0549] 以实施例3的相同方式,将制备23获得的[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯39mg(0.1mmol)和17mg(0.1mmol)4-氨基-2-氟-丁酸甲酯盐酸盐(制备3的产物)与42mg(0.2mmol)三乙酸基硼氢化钠反应,得到5.8mg标题化合物,收率37%。 [0549] In the same manner as in Example 3, the preparation of 23 [1-formyl-3-oxo-obtained 3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2 , 4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester 39mg (0.1mmol) and 17mg (0.1mmol) 4- amino-2- fluoro - butyric acid methyl ester hydrochloride (the product of preparation 3) is reacted with sodium hydride 42mg (0.2mmol) triacetoxy boron, to give 5.8mg of the title compound in 37% yield.

[0550] 1H NMR(CDCl3)δ5.7-5.9(1H,m),4.9-5.1(3H,m),3.8-4.3(5H,m),3.3-3.7(4H,m),2.4-2.8(3H,m),2.1-2.2(1H,m),1.40(9H,s), [0550] 1H NMR (CDCl3) δ5.7-5.9 (1H, m), 4.9-5.1 (3H, m), 3.8-4.3 (5H, m), 3.3-3.7 (4H, m), 2.4-2.8 ( 3H, m), 2.1-2.2 (1H, m), 1.40 (9H, s),

[0551] 质量(m/e)479(M+1) [0551] mass (m / e) 479 (M + 1)

[0552] 实施例5:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氟-吡咯烷-2-酮 [0552] Example 5: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -3-fluoro - pyrrolidin-2-one

[0553] [0553]

[0554] 以实施例3的相同方式,将制备26获得的15mg[1-(3-氟-2-氧代-吡咯烷-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到5.9mg胺,收率45%。 [0554] In the same manner as Example 3, prepared 26 15mg [1- (3- fluoro-2-oxo - pyrrolidin-l-ylmethyl) -3-oxo-obtained 3- (3- trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ethyl acetate / reaction of the ester with hydrochloric acid, to give amines 5.9mg, yield 45%.

[0555] 1H NMR(CD3OD)δ5.0-5.3(3H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.4-3.7(5H,m),2.5-2.8(3H,m),2.1-2.3(1H,m) [0555] 1H NMR (CD3OD) δ5.0-5.3 (3H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.4-3.7 (5H, m), 2.5-2.8 ( 3H, m), 2.1-2.3 (1H, m)

[0556] 质量(m/e)379(M+1) [0556] mass (m / e) 379 (M + 1)

[0557] 实施例6:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-吡咯烷-2-酮 [0557] Example 6: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] - pyrrolidin-2-one

[0558] [0558]

[0559] 将制备23获得的77mg(0.2mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯加至(23mg 0.2mmol 4-氨基-丁酸甲酯,然后所得混合物溶解于二氯乙烷,接着搅拌30分钟。其后,向其中加入84mg(0.4mmol)三乙酸基硼氢化钠,接着搅拌约2小时。浓缩后,以实施例3相同方式,残留物与乙酸乙酯/盐酸反应,得到15mg标题化合物,收率21%。 [0559] Preparation 23 The obtained 77mg (0.2mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester was added to (23mg 0.2mmol 4- amino - butyric acid methyl ester, then the resultant mixture was dissolved in dichloroethane, followed by stirring for 30 minutes. Thereafter, thereto was added 84mg (0.4mmol) of sodium borohydride triacetate group, followed by stirring for about 2 hours. after concentration, in the same manner as in Example 3, the residue and ethyl acetate / hydrochloric acid reaction, to give 15mg of the title compound, yield 21%.

[0560] 1H NMR(CD3OD)δ5.00-4.95(2H,m),4.31-4.22(2H,m),4.10-4.01(2H,m),3.74(1H,brs),3.53-3.41(3H,m),2.89-2.72(2H,m),2.37-2.34(2H,m),2.08-2.05(2H,m),1.27(2H,brs). [0560] 1H NMR (CD3OD) δ5.00-4.95 (2H, m), 4.31-4.22 (2H, m), 4.10-4.01 (2H, m), 3.74 (1H, brs), 3.53-3.41 (3H, m), 2.89-2.72 (2H, m), 2.37-2.34 (2H, m), 2.08-2.05 (2H, m), 1.27 (2H, brs).

[0561] 质量(m/e)361(M+1) [0561] mass (m / e) 361 (M + 1)

[0562] 制备27:合成[1-(3-氟-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0562] Preparation 27: Synthesis of [1- (3-fluoro-2-oxo - piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6- hydrogen -8H- [1,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0563] 以制备24的相同方式,将制备23获得的90mg(0.1mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与43mg(0.1mmol)5-氨基-2-氟-戊酸甲酯盐酸盐(制备4的产物)和98mg(0.2mmol)三乙酸基硼氢化钠反应,得到24mg标题化合物,收率21%。 [0563] In the same manner as in Preparation 24, 90mg 23 obtained in the preparation of (0.1mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 43mg (0.1mmol) 5- amino-2-fluoro - pentanoic acid methyl ester hydrochloride (the product of preparation 4) and 98mg (0.2mmol) triacetoxy sodium borohydride, to give the title compound 24mg, 21% yield.

[0564] 1H NMR(CDCl3)δ5.8-6.1(1H,m),4.6-5.2(3H,m),3.8-4.4(5H,m),3.2-3.6(4H,m),2.6-3.0(2H,m),1.7-2.1(4H,m),1.40(9H,s), [0564] 1H NMR (CDCl3) δ5.8-6.1 (1H, m), 4.6-5.2 (3H, m), 3.8-4.4 (5H, m), 3.2-3.6 (4H, m), 2.6-3.0 ( 2H, m), 1.7-2.1 (4H, m), 1.40 (9H, s),

[0565] 质量(m/e)493(M+1) [0565] mass (m / e) 493 (M + 1)

[0566] 实施例7:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氟-哌啶-2-酮 [0566] Example 7: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -3-fluoro - piperidin-2-one

[0567] [0567]

[0568] 以实施例3的相同方式,将制备27获得的24mg[1-(3-氟-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与反应,得到6mg标题化合物,收率31%。 [0568] In the same manner as Example 3, prepared 27 24mg [1- (3- fluoro-2-oxo - piperidin-1-ylmethyl) to obtain 3-oxo-3- (3- trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester with the reaction, to give 6mg of the title compound in 31% yield.

[0569] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.7-4.9(1H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.7-3.8(1H,m),3.3-3.6(4H,m),2.7-3.0(2H,m),1.8-2.2(4H,m) [0569] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.7-4.9 (1H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.8 ( 1H, m), 3.3-3.6 (4H, m), 2.7-3.0 (2H, m), 1.8-2.2 (4H, m)

[0570] 质量(m/e)393(M+1) [0570] mass (m / e) 393 (M + 1)

[0571] 制备28:合成[1-(3-甲基-2-氧代-吡咯烷-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,24,]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0571] Preparation 28: Synthesis of [1- (3-methyl-2-oxo - pyrrolidin-l-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6 dihydro -8H- [1,24,] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0572] 以制备24的相同方式,将制备25获得的75mg(0.1mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与32mg(0.1mmol)4-氨基-2-甲基-丁酸甲酯盐酸盐(制备5的产物)和81mg(0.2mmol)三乙酸基硼氢化钠反应,得到20mg标题化合物,收率22%。 [0572] In the same manner as in Preparation 24, 75mg 25 obtained in the preparation of (0.1mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 32mg (0.1mmol) 4- amino-2- yl - butyric acid methyl ester hydrochloride (the product of preparation 5) and 81mg (0.2mmol) triacetoxy sodium borohydride, to give 20mg of the title compound in a yield of 22%.

[0573] 1H NMR(CDCl3)δ5.8-6.0(1H,m),4.8-5.1(2H,m),3.8-4.3(5H,m),3.3-3.5(4H,m),2.5-2.9(2H,m),2.1-2.4(2H,m),1.5-1.6(1H,m),1.40(9H,s),1.09-1.1(3H,m) [0573] 1H NMR (CDCl3) δ5.8-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (5H, m), 3.3-3.5 (4H, m), 2.5-2.9 ( 2H, m), 2.1-2.4 (2H, m), 1.5-1.6 (1H, m), 1.40 (9H, s), 1.09-1.1 (3H, m)

[0574] 质量(m/e)475(M+1) [0574] mass (m / e) 475 (M + 1)

[0575] 实施例8:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-甲基-吡咯烷-2-酮 [0575] Example 8: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -3-methyl - pyrrolidin-2-one

[0576] [0576]

[0577] 以实施例3的相同方式,将制备28获得的20mg[1-(3-甲基-2-氧代-吡咯烷-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到4.5mg标题化合物,收率29%。 [0577] In the same manner as Example 3, prepared 28 obtained 20mg [1- (3- methyl-2-oxo - pyrrolidin-l-ylmethyl) -3-oxo-3- (3 - trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] -carbamic acid tert-1S-- butyl ester ethyl acetate / reaction with hydrochloric acid, to give 4.5mg of the title compound in 29% yield.

[0578] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.6-3.7(1H,m),3.4-3.5(4H,m),2.6-2.9(2H,m),2.2-2.5(2H,m),1.6-1.7(1H,m),1.3(1H,m),1.1-1.2(3H,m) [0578] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.6-3.7 (1H, m), 3.4-3.5 ( 4H, m), 2.6-2.9 (2H, m), 2.2-2.5 (2H, m), 1.6-1.7 (1H, m), 1.3 (1H, m), 1.1-1.2 (3H, m)

[0579] 质量(m/e)375(M+1) [0579] mass (m / e) 375 (M + 1)

[0580] 制备29:合成[1-(4-甲基-2-氧代-2,5-二氢-吡咯-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0580] Preparation 29: Synthesis of [1- (4-methyl-2-oxo-2,5-dihydro - pyrrol-1-ylmethyl) -3-oxo-3- (3-trifluoromethylsulfonyl -5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0581] 以制备24的相同方式,将制备23获得的85mg(0.22mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与36mg(0.22mmol)4-氨基-3-甲基-2-丁烯酸甲酯盐酸盐(制备6的产物)和92mg(0.44mmol)三乙酸基硼氢化钠反应,得到34mg标题化合物,收率33%。 [0581] In the same manner as in Preparation 24, the preparation obtained in 23 85mg (0.22mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 36mg (0.22mmol) 4- amino-3- methyl-2-butene hydrochloride (the product of preparation 6) and 92mg (0.44mmol) triacetoxy sodium borohydride, to give 34mg of the title compound in 33% yield.

[0582] 1H NMR(CDCl3)δ5.9-6.2(1H,m),5.72(1H,m),4.9-5.1(2H,m),3.9-4.4(7H,m),3.6-3.7(1H,m),3.4-3.5(1H,m),2.7-2.9(1H,m),2.5-2.6(1H,m),2.04(3H,s),1.38(9H,m) [0582] 1H NMR (CDCl3) δ5.9-6.2 (1H, m), 5.72 (1H, m), 4.9-5.1 (2H, m), 3.9-4.4 (7H, m), 3.6-3.7 (1H, m), 3.4-3.5 (1H, m), 2.7-2.9 (1H, m), 2.5-2.6 (1H, m), 2.04 (3H, s), 1.38 (9H, m)

[0583] 质量(m/e)473(M+1) [0583] mass (m / e) 473 (M + 1)

[0584] 实施例9:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-56-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-1,5-二氢-吡咯-2-酮 [0584] Example 9: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-dihydro -56- -8H- [1,2,4] triazolo [4, 3-a] pyrazin-7-yl) - butyl] -4-methyl-1,5-dihydro - pyrrolidin-2-one

[0585] [0585]

[0586] 以实施例3的相同方式,将制备29获得的34mg[1-(4-甲基-2-氧代-2,5-二氢-吡咯-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到25mg标题化合物,收率93%。 [0586] In the same manner as Example 3, prepared 29 obtained 34mg [1- (4- methyl-2-oxo-2,5-dihydro - pyrrol-1-ylmethyl) -3-oxo -3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] - 1S- tert - butyl ester with ethyl acetate / hydrochloric acid reaction, to give 25mg of the title compound in 93% yield.

[0587] 1H NMR(CD3OD)δ5.81(1H,m),5.0(2H,m),4.2-4.4(2H,m),4.0-4.1(4H,m),3.8-3.9(1H,m),3.65-3.75(2H,m),2.9-3.0(1H,m),2.75-2.85(1H,m),2.10(3H,s) [0587] 1H NMR (CD3OD) δ5.81 (1H, m), 5.0 (2H, m), 4.2-4.4 (2H, m), 4.0-4.1 (4H, m), 3.8-3.9 (1H, m) , 3.65-3.75 (2H, m), 2.9-3.0 (1H, m), 2.75-2.85 (1H, m), 2.10 (3H, s)

[0588] 质量(m/e)373(M+1) [0588] mass (m / e) 373 (M + 1)

[0589] 制备30:合成[1-(4-甲基-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 Preparation of [0589] 30: Synthesis of [1- (4-methyl-2-oxo - piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6 dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0590] 以制备24的相同方式,将制备25获得的85mg(0.22mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与39mg(0.22mmol)5-氨基-3-甲基-戊酸甲酯盐酸盐(制备8的产物)和92mg(0.44mmol)三乙酸基硼氢化钠反应,得到46mg标题化合物,收率43%。 [0590] In the same manner as in Preparation 24, 85mg prepared obtained 25 (0.22mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 39mg (0.22mmol) 5- amino-3- yl - pentanoic acid methyl ester hydrochloride (the product of preparation 8) and 92mg (0.44mmol) triacetoxy sodium borohydride, to give 46mg of the title compound in 43% yield.

[0591] 1H NMR(CDCl3)δ5.9-6.0(1H,m),4.8-5.1(2H,m),3.9-4.3(6H,m),3.5-3.6(1H,m),3.3-3.5(3H,m),2.7-2.9(1H,m),2.3-2.6(2H,m),1.8-1.9(2H,m),1.4-1.5(1H,m),1.39(9H,s),0.95(3H,m) [0591] 1H NMR (CDCl3) δ5.9-6.0 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (6H, m), 3.5-3.6 (1H, m), 3.3-3.5 ( 3H, m), 2.7-2.9 (1H, m), 2.3-2.6 (2H, m), 1.8-1.9 (2H, m), 1.4-1.5 (1H, m), 1.39 (9H, s), 0.95 ( 3H, m)

[0592] 质量(m/e)489(M+1) [0592] mass (m / e) 489 (M + 1)

[0593] 实施例10:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-哌啶-2-酮 [0593] Example 10: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -4-methyl - piperidin-2-one

[0594] [0594]

[0595] 以实施例3的相同方式,将制备30获得的46mg[1-(4-甲基-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到29mg标题化合物,收率79%。 [0595] In the same manner as Example 3, prepared 30 46mg [1- (4- methyl-2-oxo - piperidin-1-ylmethyl) to obtain 3-oxo-3- (3 - trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] -carbamic acid tert-1S-- butyl ester ethyl acetate / reaction with hydrochloric acid, to give 29mg of the title compound in 79% yield.

[0596] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.8-3.9(2H,m),3.3-3.8(3H,m),2.8-3.0(2H,m),2.4(1H,m),1.8-2.0(3H,m),1.5-1.6(1H,m),1.0(3H,m) [0596] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.8-3.9 (2H, m), 3.3-3.8 ( 3H, m), 2.8-3.0 (2H, m), 2.4 (1H, m), 1.8-2.0 (3H, m), 1.5-1.6 (1H, m), 1.0 (3H, m)

[0597] 质量(m/e)389(M+1) [0597] mass (m / e) 389 (M + 1)

[0598] 制备31:合成[l-(5,5-二氟-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0598] Preparation 31: Synthesis of [l- (5,5- difluoro-2-oxo - piperidin-1-ylmethyl) -3-oxo-3- (3-methyl-5, 1,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0599] 以制备24的相同方式,将制备23获得的85mg(0.22mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与44mg(0.22mmol)5-氨基-4,4-二氟-戊酸甲酯盐酸盐(制备12的产物)和92mg(0.44mmol)三乙酸基硼氢化钠反应,得到25mg标题化合物,收率23%。 [0599] In the same manner as in Preparation 24, the preparation obtained in 23 85mg (0.22mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 44mg (0.22mmol) 5- amino-4,4 - difluoro - pentanoic acid methyl ester hydrochloride (the product of preparation 12) and 92mg (0.44mmol) triacetoxy sodium borohydride, to give 25mg of the title compound in 23% yield.

[0600] 1H NMR(CDCl3)5.8-5.9(1H,m),4.8-5.1(2H,m),4.1-4.3(4H,m),3.9-4.0(1H,m),3.6-3.8(3H,m),3.3-3.5(1H,m),2.7-2.9(1H,m),2.5-2.6(2H,m),2.4(1H,t,J=7.0Hz),2.2-2.3(2H,m),1.40(9H,s) [0600] 1H NMR (CDCl3) 5.8-5.9 (1H, m), 4.8-5.1 (2H, m), 4.1-4.3 (4H, m), 3.9-4.0 (1H, m), 3.6-3.8 (3H, m), 3.3-3.5 (1H, m), 2.7-2.9 (1H, m), 2.5-2.6 (2H, m), 2.4 (1H, t, J = 7.0Hz), 2.2-2.3 (2H, m) , 1.40 (9H, s)

[0601] 质量(m/e)511(M+1) [0601] mass (m / e) 511 (M + 1)

[0602] 实施例11:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5,5-二氟-哌啶-2-酮 [0602] Example 11: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -5,5-difluoro - piperidin-2-one

[0603] [0603]

[0604] 以实施例3的相同方式,将制备31获得的25mg[1-(5,5-二氟-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到7.9mg标题化合物,收率39%。 [0604] In the same manner as Example 3, prepared 31 25mg [1- (5,5- difluoro-2-oxo - piperidin-1-ylmethyl) -3-oxo-3- obtained (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] carbamic acid 1S- tert - butyl ester ethyl acetate / reaction with hydrochloric acid, to give 7.9mg of the title compound in 39% yield.

[0605] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.7-3.9(2H,m),3.6-3.7(2H,m),3.4-3.5(1H,m),2.8(1H,td,J=16,5Hz),2.6-2.7(1H,m),2.5-2.6(2H,m),2.3-2.4(2H,m) [0605] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.9 (2H, m), 3.6-3.7 ( 2H, m), 3.4-3.5 (1H, m), 2.8 (1H, td, J = 16,5Hz), 2.6-2.7 (1H, m), 2.5-2.6 (2H, m), 2.3-2.4 (2H , m)

[0606] 质量(m/e)411(M+1) [0606] mass (m / e) 411 (M + 1)

[0607] 制备32:合成[1-(5R-甲基-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0607] Preparation 32: Synthesis of [1- (5R--2-oxo - piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6 dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0608] 以制备24的相同方式,将制备23获得的80mg(0.20mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与37mg(0.20mmol)(R)-5-氨基-4-甲基-戊酸甲酯盐酸盐(制备7的产物)和87mg(0.40mmol)三乙酸基硼氢化钠反应,得到33mg标题化合物,收率33%。 [0608] In the same manner as in Preparation 24, the preparation obtained in 23 80mg (0.20mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 37mg (0.20mmol) (R) -5- amino -4-methyl - pentanoic acid methyl ester hydrochloride (the product of preparation 7) and 87mg (0.40mmol) triacetoxy sodium borohydride, to give 33mg of the title compound in 33% yield.

[0609] 1H NMR(CDCl3)δ5.9-6.0(1H,m),4.8-5.1(2H,m),3.8-4.3(5H,m),3.2-3.7(3H,m),2.9-3.1(1H,m),2.1-2.9(4H,m),1.7-2.0(2H,m),1.3-1.5(1H,m),1.40(9H,s),0.98(3H,m) [0609] 1H NMR (CDCl3) δ5.9-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (5H, m), 3.2-3.7 (3H, m), 2.9-3.1 ( 1H, m), 2.1-2.9 (4H, m), 1.7-2.0 (2H, m), 1.3-1.5 (1H, m), 1.40 (9H, s), 0.98 (3H, m)

[0610] 质量(m/e)489(M+1) [0610] mass (m / e) 489 (M + 1)

[0611] 实施例12:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5R-甲基-哌啶-2-酮 [0611] Example 12: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] 5R-methyl - piperidin-2-one

[0612] [0612]

[0613] 以实施例3的相同方式,将制备32获得的33mg[1-(5R-甲基-2-氧代-哌啶-1-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到15.3mg标题化合物,收率58%。 [0613] In the same manner as Example 3, prepared 32 33mg [1- (5R--2-oxo - piperidin-1-ylmethyl) to obtain 3-oxo-3- (3 - trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] -carbamic acid tert-1S-- butyl ester ethyl acetate / reaction with hydrochloric acid, to give 15.3mg of the title compound in 58% yield.

[0614] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.8-3.9(1H,m),3.7-3.8(1H,m),3.55-3.65(1H,m),3.3-3.4(1H,m),2.8-3.1(3H,m),2.3-2.4(2H,m),2.0-2.1(1H,m),1.8-1.9(1H,m),1.5-1.6(1H,m),1.03(3H,d,J=6Hz) [0614] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.8-3.9 (1H, m), 3.7-3.8 ( 1H, m), 3.55-3.65 (1H, m), 3.3-3.4 (1H, m), 2.8-3.1 (3H, m), 2.3-2.4 (2H, m), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.03 (3H, d, J = 6Hz)

[0615] 质量(m/e)389(M+1) [0615] mass (m / e) 389 (M + 1)

[0616] 制备33:合成[3-氧代-1-(2-氧代-4-三氟甲基-吡咯烷-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0616] Preparation 33: Synthesis of [3-oxo-1- (2-oxo-4-trifluoromethyl - pyrrolidin-l-ylmethyl) -3- (3-methyl-5-trifluoromethyl, 1,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0617] 以制备24的相同方式,将制备23获得的80mg(0.20mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与48mg(0.20mmol)3-氨基甲基-4,4,4-三氟-丁酸乙酯盐酸盐(制备1的产物)和87mg(0.40mmol)三乙酸基硼氢化钠反应,得到4.6mg标题化合物,收率40%。 [0617] In the same manner as in Preparation 24, the preparation obtained in 23 80mg (0.20mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 48mg (0.20mmol) 3- amino-4 , 4,4-trifluoro - butyric acid ethyl ester hydrochloride (the product of preparation 1) and 87mg (0.40mmol) triacetoxy sodium borohydride, to give 4.6mg of the title compound in 40% yield.

[0618] 1H NMR(CDCl3)δ5.6-5.7(1H,m),4.8-5.1(2H,m),3.9-4.3(5H,m),3.3-3.8(4H,m),3.0-3.1(1H,m),2.4-2.9(4H,m),1.4(9H,s) [0618] 1H NMR (CDCl3) δ5.6-5.7 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (5H, m), 3.3-3.8 (4H, m), 3.0-3.1 ( 1H, m), 2.4-2.9 (4H, m), 1.4 (9H, s)

[0619] 质量(m/e)529(M+1) [0619] mass (m / e) 529 (M + 1)

[0620] 实施例13:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-三氟甲基-吡咯烷-2-酮 [0620] Example 13: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -4-trifluoromethyl - pyrrolidin-2-one

[0621] [0621]

[0622] 以实施例3的相同方式,将制备33获得的18mg[3-氧代-1-(2-氧代-4-三氟甲基-吡咯烷-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到7mg标题化合物,收率48%。 [0622] In the same manner as Example 3, prepared 33 18mg [3- obtained oxo-1- (2-oxo-4-trifluoromethyl - pyrrolidin-l-ylmethyl) -3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] carbamic acid 1S- tert - butyl ester ethyl acetate / reaction with hydrochloric acid, to obtain 7mg of the title compound in 48% yield.

[0623] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.7-3.9(2H,m),3.5-3.7(3H,m),3.3-3.4(1H,m),2.8-3.0(2H,m),2.5-2.7(2H,m) [0623] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.9 (2H, m), 3.5-3.7 ( 3H, m), 3.3-3.4 (1H, m), 2.8-3.0 (2H, m), 2.5-2.7 (2H, m)

[0624] 质量(m/e)429(M+1) [0624] mass (m / e) 429 (M + 1)

[0625] 制备34:合成[3-氧代-1-(2-氧代-4-三氟甲基-哌啶-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0625] Preparation 34: Synthesis of [3-oxo-1- (2-oxo-4-trifluoromethyl - piperidin-1-ylmethyl) -3- (3-methyl-5-trifluoromethyl, 1,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0626] 以制备24的相同方式,将制备23获得的80mg(0.20mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与51mg(0.20mmol)5-氨基-3-三氟甲基-戊酸乙酯盐酸盐(制备11的产物)和87mg(0.40mmol)三乙酸基硼氢化钠反应,得到41mg标题化合物,收率37%。 [0626] In the same manner as in Preparation 24, the preparation obtained in 23 80mg (0.20mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 51mg (0.20mmol) 5- amino-3 fluoromethyl - pentanoic acid ethyl ester hydrochloride (product of preparation 11) and 87mg (0.40mmol) triacetoxy sodium borohydride, to give 41mg of the title compound in 37% yield.

[0627] 1H NMR(CDCl3)δ5.7-6.0(1H,m),4.8-5.1(2H,m),3.8-4.3(5H,m),3.3-3.7(4H,m),2.7-2.9(1H,m),2.4-2.6(3H,m),2.3-2.4(1H,m),2.1(1H,m),1.8(1H,m),1.4(9H,s) [0627] 1H NMR (CDCl3) δ5.7-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (5H, m), 3.3-3.7 (4H, m), 2.7-2.9 ( 1H, m), 2.4-2.6 (3H, m), 2.3-2.4 (1H, m), 2.1 (1H, m), 1.8 (1H, m), 1.4 (9H, s)

[0628] 质量(m/e)543(M+1) [0628] mass (m / e) 543 (M + 1)

[0629] 实施例14:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-三氟甲基-哌啶-2-酮 [0629] Example 14: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -4-trifluoromethyl - piperidin-2-one

[0630] [0630]

[0631] 以实施例3的相同方式,将制备34获得的41mg[3-氧代-1-(2-氧代-4-三氟甲基-哌啶-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到28.3mg标题化合物,收率85%。 [0631] In the same manner as Example 3, prepared 41mg [3- obtained 34-oxo-1- (2-oxo-4-trifluoromethyl - piperidin-1-ylmethyl) -3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] carbamic acid 1S- tert - butyl ester ethyl acetate / reaction with hydrochloric acid, to give 28.3mg of the title compound in 85% yield.

[0632] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.7-3.9(2H,m),3.4-3.7(3H,m),2.8-3.1(3H,m),2.5-2.7(1H,m),2.3-2.5(1H,m),2.1-2.2(1H,m),1.8-2.0(1H,m),1.3(1H,m) [0632] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.9 (2H, m), 3.4-3.7 ( 3H, m), 2.8-3.1 (3H, m), 2.5-2.7 (1H, m), 2.3-2.5 (1H, m), 2.1-2.2 (1H, m), 1.8-2.0 (1H, m), 1.3 (1H, m)

[0633] 质量(m/e)443(M+1) [0633] mass (m / e) 443 (M + 1)

[0634] 制备35:-[3-氧代-1-(2-氧代-5-三氟甲基-哌啶-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0634] Preparation 35: - [3-oxo-1- (2-oxo-5-trifluoromethyl - piperidin-1-ylmethyl) -3- (3-methyl-5-trifluoromethyl, 1,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0635] 以制备24的相同方式,将制备23获得的286mg(0.73mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与172mg(0.73mmol)4-氨基甲基-5,5,5-三氟-戊酸甲酯盐酸盐(制备9的产物)和310mg(1.46mmol)三乙酸基硼氢化钠反应,得到260mg标题化合物,收率37%。 [0635] In the same manner as in Preparation 24, the preparation obtained 286mg 23 (0.73mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 172mg (0.73mmol) 4- aminomethyl -5 , 5,5-trifluoro - pentanoic acid methyl ester hydrochloride (the product of preparation 9) and 310mg (1.46mmol) triacetoxy sodium borohydride, to give 260mg of the title compound in 37% yield.

[0636] 1H NMR(CDCl3)δ5.7-6.0(1H,m),4.8-5.1(2H,m),4.1-4.3(4H,m),3.7-4.0(2H,m),3.3-3.7(3H,m),2.2-2.9(5H,m),2.0-2.1(1H,m),1.8-1.9(1H,m),1.39(9H,s) [0636] 1H NMR (CDCl3) δ5.7-6.0 (1H, m), 4.8-5.1 (2H, m), 4.1-4.3 (4H, m), 3.7-4.0 (2H, m), 3.3-3.7 ( 3H, m), 2.2-2.9 (5H, m), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.39 (9H, s)

[0637] 质量(m/e)543(M+1) [0637] mass (m / e) 543 (M + 1)

[0638] 实施例15:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5-三氟甲基-哌啶-2-酮 [0638] Example 15: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -5-trifluoromethyl - piperidin-2-one

[0639] [0639]

[0640] 以实施例3的相同方式,将制备35获得的260mg[3-氧代-1-(2-氧代-5-三氟甲基-哌啶-1-基甲基)-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到15mg标题化合物,收率7%。 [0640] In the same manner as Example 3, prepared 35 260mg [3- obtained oxo-1- (2-oxo-5-trifluoromethyl - piperidin-1-ylmethyl) -3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] carbamic acid 1S- tert - butyl ester ethyl acetate / reaction with hydrochloric acid, to give the title compound 15mg, 7% yield.

[0641] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.0-4.2(2H,m),3.8-3.9(2H,m),3.4-3.8(3H,m),2.8-3.0(3H,m),2.4-2.5(2H,m),2.0-2.1(1H,m),1.8-2.0(1H,m) [0641] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.8-3.9 (2H, m), 3.4-3.8 ( 3H, m), 2.8-3.0 (3H, m), 2.4-2.5 (2H, m), 2.0-2.1 (1H, m), 1.8-2.0 (1H, m)

[0642] 质量(m/e)443(M+1) [0642] mass (m / e) 443 (M + 1)

[0643] 制备36:合成[1-(2-甲基-5-氧代-吗啉-4-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0643] Preparation 36: Synthesis of [1- (2-methyl-5-oxo - morpholin-4-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6 dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0644] 以制备24的相同方式,将制备23获得的140mg(0.36mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与71mg(0.36mmol)(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐(制备10的产物)和151mg(0.72mmol)三乙酸基硼氢化钠反应,得到78mg标题化合物,收率44%。 [0644] In the same manner as in Preparation 24, prepared 23 140mg (0.36mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro obtained -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 71mg (0.36mmol) (2- amino-1- - methyl-ethoxy) - acetate hydrochloride (the product of preparation 10) 151mg (0.72mmol) of sodium borohydride triacetate base and reaction, to give 78mg of the title compound in 44% yield.

[0645] 1H NMR(CDCl3)δ5.8-6.0(1H,m),4.8-5.1(2H,m),3.9-4.3(7H,m),3.7-3.9(1H,m),3.5-3.7(1H,m),3.1-3.5(3H,m),2.5-2.9(2H,m),1.33(9H,s),1.19(3H,br s) [0645] 1H NMR (CDCl3) δ5.8-6.0 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (7H, m), 3.7-3.9 (1H, m), 3.5-3.7 ( 1H, m), 3.1-3.5 (3H, m), 2.5-2.9 (2H, m), 1.33 (9H, s), 1.19 (3H, br s)

[0646] 质量(m/e)491(M+1) [0646] mass (m / e) 491 (M + 1)

[0647] 实施例16:合成4-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-6-甲基-吗啉-3-酮 [0647] Example 16: Synthesis of 4- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [ 4,3-a] pyrazin-7-yl) - butyl] -6-methyl - morpholin-3-one

[0648] [0648]

[0649] 以实施例3的相同方式,将制备36获得的78mg[1-(2-甲基-5-氧代-吗啉-4-基甲基)-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到25.7mg标题化合物,收率451%。 [0649] In the same manner as Example 3, prepared 36 78mg [1- obtained (2-methyl-5-oxo - morpholin-4-ylmethyl) -3-oxo-3- (3 - trifluoromethyl-5,6-dihydro--8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] -carbamic acid tert-1S-- butyl ester ethyl acetate / reaction with hydrochloric acid, to give 25.7mg of the title compound in a yield of 451%.

[0650] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.2-4.4(2H,m),4.1-4.2(2H,m),3.8-4.1(4H,m),3.68(1H,m),3.2-3.5(3H,m),2.8-3.1(2H,m),1.24(3H,d,J=6.5Hz) [0650] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.1-4.2 (2H, m), 3.8-4.1 (4H, m), 3.68 (1H, m), 3.2-3.5 (3H, m), 2.8-3.1 (2H, m), 1.24 (3H, d, J = 6.5Hz)

[0651] 质量(m/e)391(M+1) [0651] mass (m / e) 391 (M + 1)

[0652] 制备37:合成[1-(叔-丁基-二甲基-硅烷基氧基甲基-3-(3.4-二氢-1H-异喹啉-2-基)-3-氧代-丙基)-1S-氨基甲酸叔-丁酯 [0652] Preparation 37: Synthesis of [1- (tert - butyl - dimethyl - silanyloxymethyl 3- (3.4-dihydro -1H- isoquinolin-2-yl) -3-oxo - propyl) 1S-carbamic acid tert - butyl ester

[0653] 以制备22-(2)的相同方式,将制备22(1)获得的100mg 3S-叔-丁氧基羧基氨基-4-(叔-丁基-二甲基-硅烷基氧基)-丁酸与1101 3,4-二氢-1H-异喹啉反应,得到34mg标题化合物,收率87%。 [0653] In the same manner as the preparation of 22- (2), of Preparation 22 (1) 100mg 3S- obtained tert - butoxy-carboxy-4- (tert - butyl - dimethyl - silanyloxy) - butyric acid -1H- dihydro-isoquinoline is reacted with 3,4-1101, to give 34mg of the title compound in 87% yield.

[0654] 1H NMR(CDCl3)δ7.1-7.3(4H,m),5.5-5.6(1H,m),4.7-4.8(2H,m),4.0-4.1(1H,m),3.6-3.9(4H,m),2.8-3.0(3H,m),2.6-2.7(1H,m),1.47(9H,s),0.92(9H,s),0.19(3H,s),0.14(3H,s) [0654] 1H NMR (CDCl3) δ7.1-7.3 (4H, m), 5.5-5.6 (1H, m), 4.7-4.8 (2H, m), 4.0-4.1 (1H, m), 3.6-3.9 ( 4H, m), 2.8-3.0 (3H, m), 2.6-2.7 (1H, m), 1.47 (9H, s), 0.92 (9H, s), 0.19 (3H, s), 0.14 (3H, s)

[0655] 质量(m/e)449(M+1) [0655] mass (m / e) 449 (M + 1)

[0656] 制备38:合成[3-(3,4-二氢-1H-异喹啉-2-基)-1-甲酰基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯 [0656] Preparation 38: Synthesis of [3- (3,4-dihydro -1H- isoquinolin-2-yl) -1-Formyl-3-oxo - propyl] amino-1S-tert - butyl ester

[0657] (1)合成[3-(3,4-二氢-1H-异喹啉-2-基)-1-羟基甲基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯 [0657] (1) Synthesis of [3- (3,4-dihydro -1H- isoquinolin-2-yl) -1-hydroxy-3-oxo - propyl] -carbamic acid tert-1S-- butyl

[0658] 利用制备37获得的349mg[1-(叔-丁基-二甲基-硅烷基氧基甲基)-3-(3,4-二氢-1H-异喹啉-2-基)-3-氧代-丙基)-1S-氨基甲酸叔-丁酯,以制备23-(1)的相同方式,获得250mg[3-(3,4-二氢-1H-异喹啉-2-基)-1-羟基甲基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯,收率96%。 [0658] prepared using 37 349mg [1- (tert - butyl - dimethyl - silanyloxymethyl) obtained 3- (3,4-dihydro -1H- isoquinolin-2-yl) 3-oxo - propyl) 1S-tert - butyl ester, prepared 23- (1) in the same manner to obtain 250mg [3- (3,4- dihydro-iso quinolin-2 -1H- - yl) -1-hydroxy-3-oxo - propyl] amino-1S-tert - butyl ester, 96% yield.

[0659] 1H NMR(CDCl3)δ7.1-7.2(4H,m),5.5-5.6(1H,m),4.6-4.8(2H,m),3.7-4.0(5H,m),3.3-3.4(2H,m),2.7-3.0(2H,m),1.41(9H,s),0.90(9H,s),0.10(6H,s) [0659] 1H NMR (CDCl3) δ7.1-7.2 (4H, m), 5.5-5.6 (1H, m), 4.6-4.8 (2H, m), 3.7-4.0 (5H, m), 3.3-3.4 ( 2H, m), 2.7-3.0 (2H, m), 1.41 (9H, s), 0.90 (9H, s), 0.10 (6H, s)

[0660] 质量(m/e)357(M+Na) [0660] mass (m / e) 357 (M + Na)

[0661] (2)合成[3-(3,4-二氢-1H-异喹啉-2-基)-1-甲酰基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯 [0661] (2) Synthesis of [3- (3,4-dihydro -1H- isoquinolin-2-yl) -1-Formyl-3-oxo - propyl] amino-1S-tert - butyl ester

[0662] 以实施例3的相同方式,将用与制备23-(2)的相同方式获得的250mg[3-(3,4-二氢-1H-异喹啉-2-基)-1-羟基甲基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯(步骤1的产物)与10mL Dess-Martin(~0.3M)反应,得到180mg标题化合物,收率72%。 [0662] In the same manner as Example 3, with the preparation of 23- 250mg [3- (2) obtained in the same manner as (3,4-dihydro -1H- isoquinolin-2-yl) -1- hydroxy-3-oxo - propyl] 1S-carbamic acid tert - butyl ester (product of step 1) with 10mL Dess-Martin (~ 0.3M) to give the title compound 180mg, 72% yield.

[0663] 1H NMR(CDCl3)δ9.72(1H,s),7.1-7.2(4H,m),5.97(1H,m),4.3-4.8(4H,m),3.6-3.8(2H,m),2.8-3.0(2H,m),1.45(9H,s) [0663] 1H NMR (CDCl3) δ9.72 (1H, s), 7.1-7.2 (4H, m), 5.97 (1H, m), 4.3-4.8 (4H, m), 3.6-3.8 (2H, m) , 2.8-3.0 (2H, m), 1.45 (9H, s)

[0664] 质量(m/e)333(M+1) [0664] mass (m / e) 333 (M + 1)

[0665] 制备39:合成[3-(3,4-二氢-1H-异喹啉-2-基)-3-氧代-1-(2-氧代-哌啶-1-基甲基)-丙基]-1S-氨基甲酸叔-丁酯 [0665] Preparation 39: Synthesis of [3- (3,4-dihydro -1H- isoquinolin-2-yl) -3-oxo-1- (2-oxo - piperidin-1-yl-methyl ) - propyl] 1S-carbamic acid tert - butyl ester

[0666] 以制备24的相同方式,将制备30获得的60mg(0.18mmol)[3-(3,4-二氢-1H-异喹啉-2-基)-1-甲酰基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯与5-氨基-戊酸甲酯盐酸盐mmol和77mg(0.36mmol)三乙酸基硼氢化钠反应,得到9mg标题化合物,收率12%。 [0666] In the same manner as in Preparation 24, prepared 30 60mg (0.18mmol) obtained [3- (3,4-dihydro -1H- isoquinolin-2-yl) -1-oxo-3- Generation - propyl] 1S-carbamic acid tert - butyl ester and 5-amino - mmol pentanoate hydrochloride and 77mg (0.36mmol) triacetoxy sodium borohydride, to give 9mg of the title compound, yield 12% .

[0667] 质量(m/e)416(M+1) [0667] mass (m / e) 416 (M + 1)

[0668] 实施例17:合成1-[2S-氨基-4-(3,4-二氢-1H-异喹啉-2-基)-4-氧代-丁基]-哌啶-2-酮 [0668] Example 17: Synthesis of 1- [2S- Amino-4- (3,4-dihydro -1H- isoquinolin-2-yl) -4-oxo - butyl] - piperidine-2 ketone

[0669] [0669]

[0670] 以实施例3的相同方式,将制备39获得的9mg[3-(3,4-二氢-1H-异喹啉-2-基)-3-氧代-1-(2-氧代-哌啶-1-基甲基)-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到4.4mg标题化合物,收率64%。 [0670] In the same manner as Example 3, prepared 39 9mg [3- (3,4- dihydro -1H- isoquinolin-2-yl) -3-oxo obtained in (2-oxo Generation - piperidin-1-yl-methyl) - propyl] amino-1S-tert - butyl ester and ethyl acetate / hydrochloric acid reaction, to give 4.4mg of the title compound in 64% yield.

[0671] 1H NMR(CD3OD)δ7.1-7.2(4H,m),4.67(2H,d,J=13Hz),3.6-3.8(4H,m),3.3-3.5(3H,m),2.8-3.0(3H,m),2.6-2.7(1H,m),2.3-2.4(2H,m),1.7-1.9(4H,m) [0671] 1H NMR (CD3OD) δ7.1-7.2 (4H, m), 4.67 (2H, d, J = 13Hz), 3.6-3.8 (4H, m), 3.3-3.5 (3H, m), 2.8- 3.0 (3H, m), 2.6-2.7 (1H, m), 2.3-2.4 (2H, m), 1.7-1.9 (4H, m)

[0672] 质量(m/e)316(M+1) [0672] mass (m / e) 316 (M + 1)

[0673] 制备40:合成[3-(3,4-二氢-1H-异喹啉-2-基)-1-(4-甲基-2-氧代-吡咯烷-1-基甲基)-3-氧代-丙基]-1S-氨基甲酸叔-丁酯 [0673] Preparation 40: Synthesis of [3- (3,4-dihydro -1H- isoquinolin-2-yl) -1- (4-methyl-2-oxo - pyrrolidin-l-ylmethyl ) -3-oxo - propyl] 1S-carbamic acid tert - butyl ester

[0674] 以制备24的相同方式,将制备38获得的59mg(0.18mmol)[3-(3,4-二氢-1H-异喹啉-2-基)-1-甲酰基-3-氧代-丙基]-1S-氨基甲酸叔-丁酯与30mg(0.18mmol)4-氨基-3-甲基-丁酸甲酯和77mg(0.36mmol)三乙酸基硼氢化钠反应,得到20mg标题化合物,收率27%。 [0674] In the same manner as in Preparation 24, prepared 38 59mg (0.18mmol) obtained [3- (3,4-dihydro -1H- isoquinolin-2-yl) -1-oxo-3- Generation - propyl] 1S-carbamic acid tert - butyl ester and 30mg (0.18mmol) 4- amino-3-methyl - butyric acid methyl ester and 77mg (0.36mmol) triacetoxy sodium borohydride, to give 20mg of the title compound in 27% yield.

[0675] 质量(m/e)416(M+1) [0675] mass (m / e) 416 (M + 1)

[0676] 实施例18:合成1-[2S-氨基-4-(3,4-二氢-1H-异喹啉-2-基)-4-氧代-丁基]-4-甲基-吡咯烷-2-酮 [0676] Example 18: Synthesis of 1- [2S- Amino-4- (3,4-dihydro -1H- isoquinolin-2-yl) -4-oxo - butyl] -4-methyl - pyrrolidin-2-one

[0677] [0677]

[0678] 以实施例3的相同方式,将制备40获得的20mg[3-(3,4-二氢-1H-异喹啉-2-基)-1-(4-甲基-2-氧代-吡咯烷-1-基甲基)-3-氧代-丙基]-1S-氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应,得到11mg标题化合物,收率72%。 [0678] In the same manner as Example 3, prepared 20mg [3- 40 obtained (3,4-dihydro -1H- isoquinolin-2-yl) -1- (4-methyl-2-oxo Generation - pyrrolidin-l-ylmethyl) -3-oxo - propyl] 1S-carbamic acid tert - butyl ester and ethyl acetate / hydrochloric acid to give the title compound 11mg, 72% yield.

[0679] 1H NMR(CD3OD)δ7.1-7.2(4H,m),4.67(2H,d,J=13Hz),3.6-3.8(4H,m),3.5(1H,d,J=6Hz),3.3-3.4(1H,m),3.0-3.2(1H,m),2.8-3.0(3H,m),2.6-2.8(1H,m),2.4-2.6(2H,m),2.0-2.1(1H,m),1.1(3H,m) [0679] 1H NMR (CD3OD) δ7.1-7.2 (4H, m), 4.67 (2H, d, J = 13Hz), 3.6-3.8 (4H, m), 3.5 (1H, d, J = 6Hz), 3.3-3.4 (1H, m), 3.0-3.2 (1H, m), 2.8-3.0 (3H, m), 2.6-2.8 (1H, m), 2.4-2.6 (2H, m), 2.0-2.1 (1H , m), 1.1 (3H, m)

[0680] 质量(m/e)316(M+1) [0680] mass (m / e) 316 (M + 1)

[0681] 制备41:合成3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯 [0681] Preparation 41: Synthesis of 3S- tert - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester

[0682] 将0.69mL(9.72mmol)二甲基亚砜溶解于20mL二氯甲烷,并通过干冰/丙酮冷却至-78℃,然后向其中缓慢加入0.42mL(4.81mmol)草酰氯。 [0682] A 0.69mL (9.72mmol) was dissolved in dimethylsulfoxide 20mL of dichloromethane, and dry ice / acetone cooled to -78 deg.] C, and then slowly added 0.42 mL (4.81 mmol) of oxalyl chloride. 20分钟之后,向所得溶液在相同温度下缓慢加入述溶液5分钟:将参照J.Med.Chem.1999,42,3557-3571用Boc-L-Asp(O-tBu)-OH合成的666mg(2.42mmol)3S-叔-丁氧基羰基氨基-4-羟基-丁酸叔-丁酯溶解于9mL二氯甲烷形成的溶液。 After 20 minutes, the resulting solution was slowly added to the above solution for 5 minutes at the same temperature: with reference to J.Med.Chem.1999,42,3557-3571 Boc-L-Asp (O-tBu) -OH synthesized 666 mg ( 2.42mmol) 3S- tert - butoxycarbonyl-4-hydroxy - butyric acid tert - butyl ester was dissolved in a solution of methylene chloride at 9mL. 相同温度下搅拌20分钟后,将2.0mL三乙胺(11.7mmol)溶解于5mL二氯甲烷形成的溶液用5分钟滴加至反应液。 After stirring at the same temperature for 20 min, 2.0mL triethylamine (11.7 mmol) was dissolved in 5mL of dichloromethane was added dropwise to the reaction solution for 5 minutes. 其后,温度逐渐升高至-70℃,反应液以二乙基醚稀释,然后分别用0.5N KHSO4水溶液、水和NaCl水溶液洗涤一次。 Thereafter, the temperature was gradually raised to -70 deg.] C, the reaction was diluted with diethyl ether, and then were washed with 0.5N KHSO4 solution, water and aqueous NaCl solution. 有机层用无水硫酸镁干燥,过滤,再浓缩,得到标题化合物。 The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound. 该化合物可用于下次反应,无需进一步纯化。 The compounds can be used in the next reaction without further purification.

[0683] 1H NMR(CDCl3)δ9.65(1H,s),5.65(1H,brs),4.54(1H,brs),2.92-2.72(2H,m),1.52-1.44(18H,m) [0683] 1H NMR (CDCl3) δ9.65 (1H, s), 5.65 (1H, brs), 4.54 (1H, brs), 2.92-2.72 (2H, m), 1.52-1.44 (18H, m)

[0684] 质量(m/e)274(M+1) [0684] mass (m / e) 274 (M + 1)

[0685] 制备42:合成3S-叔-丁氧基羰基氨基-4-(2-氧代-哌啶-1-基)-丁酸叔-丁酯 [0685] Preparation 42: Synthesis of 3S- tert - butoxycarbonylamino-4- (2-oxo - piperidin-1-yl) - butanoic acid tert - butyl ester

[0686] 将576mg(3.44mg)5-氨基-戊酸甲酯盐酸盐溶解于1,2-二氯乙烷5mL形成的溶液室温下加至下述溶液:1.80g 3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯(制备41的产物)溶解于50mL 1,2-二氯乙烷形成的溶液。 [0686] A 576mg (3.44mg) 5- amino - pentanoic acid methyl ester hydrochloride salt was dissolved in 1,2-dichloroethane at room temperature the solution formed was added to 5mL following solution: 1.80g 3S- tert - butoxy benzyloxycarbonylamino-4-oxo - butyric acid tert - butyl ester (the product of preparation 41) was dissolved in 50 mL 1,2-dichloroethane was formed. 室温下搅拌15分钟之后,向其中加入1.46g(6.88mmol)三乙酸基硼氢化钠。 After stirring at room temperature for 15 minutes, and thereto 1.46g (6.88mmol) triacetoxy sodium borohydride. 室温下搅拌5小时之后,所得溶液以methyl chloridem稀释,然后依序用1N盐酸水溶液和盐水洗涤。 After stirring at room temperature for 5 hours, the resulting solution was diluted with methyl chloridem, then sequentially washed with 1N aqueous hydrochloric acid solution and brine. 如此获得的有机层用无水硫酸镁干燥,减压下蒸馏掉溶剂,然后经减压浓缩获得的残留物通过柱层析纯化,得到568mg标题化合物,总收率46%。 The organic layer thus obtained was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then concentrated under reduced pressure The residue obtained was purified by column chromatography to give the title compound 568mg, 46% overall yield.

[0687] 1H NMR(CDCl3)δ5.34-5.29(1H,m),4.17(1H,brs),3.92-3.84(1H,m),3.51-3.46(1H,m),3.27-3.23(1H,m),3.10-3.05(1H,m),2.56-2.51(1H,m),2.41-2.31(3H,m),1.82-1.75(4H,m),1.45(9H,s) [0687] 1H NMR (CDCl3) δ5.34-5.29 (1H, m), 4.17 (1H, brs), 3.92-3.84 (1H, m), 3.51-3.46 (1H, m), 3.27-3.23 (1H, m), 3.10-3.05 (1H, m), 2.56-2.51 (1H, m), 2.41-2.31 (3H, m), 1.82-1.75 (4H, m), 1.45 (9H, s)

[0688] 质量(m/e)357(M+1) [0688] mass (m / e) 357 (M + 1)

[0689] 制备43:合成3S-叔-丁氧基羰基氨基-4-(2-氧代-哌啶-1-基)-丁酸 [0689] Preparation 43: Synthesis of 3S- tert - butoxycarbonylamino-4- (2-oxo - piperidin-1-yl) - butanoic acid

[0690] (1)合成3S-氨基-4-(2-氧代-哌啶-1-基)-丁酸 [0690] (1) Synthesis of 3S- amino-4- (2-oxo - piperidin-1-yl) - butanoic acid

[0691] 将制备42获得的214mg(0.60mmol)叔-丁氧基羰基氨基-4-(2-氧代-哌啶-1-基)-丁酸叔-丁酯溶解于2mL二氯甲烷(hloromethane)/三氟乙酸(1/1)溶液,接着室温下搅拌18小时。 [0691] The preparation obtained in 42 214mg (0.60 mmol) tert - butoxycarbonylamino-4- (2-oxo - piperidin-1-yl) - butanoic acid tert - butyl ester was dissolved in 2mL dichloromethane ( hloromethane) / trifluoroacetic acid (1/1) solution, followed by stirring at room temperature for 18 hours. 减压下除去过量三氟乙酸和二氯甲烷,得到280mg标题化合物。 Excess trifluoroacetic acid was removed and the methylene chloride under reduced pressure to give 280mg of the title compound. 该化合物用于下一反应,无需任何的进一步纯化。 This compound was used in the next reaction without any further purification.

[0692] 1H NMR(CD3OD)δ4.00-3.77(2H,m),3.48-3.38(3H,m),2.80-2.70(2H,s),2.43-2.40(2H,m),1.89-1.82(4H,m) [0692] 1H NMR (CD3OD) δ4.00-3.77 (2H, m), 3.48-3.38 (3H, m), 2.80-2.70 (2H, s), 2.43-2.40 (2H, m), 1.89-1.82 ( 4H, m)

[0693] 质量(m/e)200(M+1) [0693] mass (m / e) 200 (M + 1)

[0694] (2)合成3S-叔-丁氧基羰基氨基-4-(2-氧代-哌啶-1-基)-丁酸 [0694] (2) Synthesis of 3S- tert - butoxycarbonylamino-4- (2-oxo - piperidin-1-yl) - butanoic acid

[0695] 将上述步骤(1)获得的280mg 3S-氨基-4-(2-氧代-哌啶-1-基)-丁酸溶解于10mL水/1,4-二噁烷(1/1)溶剂,接着加入144mg(0.66mmol)二碳酸二叔-丁酯。 [0695] The above step (1) obtained 280mg 3S- amino-4- (2-oxo - piperidin-1-yl) - butanoic acid was dissolved in 10mL of water / 1,4-dioxane (1/1 ) solvent, followed by addition of 144mg (0.66mmol) of di-tert - butyl. 向其中加入2.3mL 1N氢氧化钠水溶液,然后室温下搅拌18小时。 To this was added 2.3mL 1N aqueous sodium hydroxide solution, followed by stirring at room temperature for 18 hours. 反应液以二氯甲烷稀释,有机层分别用1N盐酸水溶液和NaCl水溶液洗涤一次,用无水硫酸镁干燥,接着过滤,减压下浓缩。 The reaction solution was diluted with dichloromethane, the organic layer was washed with 1N aqueous hydrochloric acid and once with aqueous NaCl solution, dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure. 所得化合物分离,残留物通过柱层析纯化,得到110mg标题化合物,收率61%。 The resulting compound was separated, the residue was purified by column chromatography to give 110mg of the title compound in 61% yield.

[0696] 1H NMR(CD3OD)δ4.28-4.25(1H,m),3.67-3.58(1H,m),3.54-3.49(1H,m),3.40-3.32(3H,m),2.59-2.47(2H,m),2.37-2.30(2H,m),1.83-1.81(4H,m),1.44(9H,s). [0696] 1H NMR (CD3OD) δ4.28-4.25 (1H, m), 3.67-3.58 (1H, m), 3.54-3.49 (1H, m), 3.40-3.32 (3H, m), 2.59-2.47 ( 2H, m), 2.37-2.30 (2H, m), 1.83-1.81 (4H, m), 1.44 (9H, s).

[0697] 质量(m/e)301(M+1) [0697] mass (m / e) 301 (M + 1)

[0698] 制备44:合成3-三氟甲基-4,5,6,7-四氢-异噁唑[3,4-c]吡啶 [0698] Preparation 44: Synthesis of 3-trifluoromethyl-4,5,6,7-tetrahydro - isoxazole [3,4-c] pyridine

[0699] 将参照WO 04/064778获得的365mg(1.24mmol)3-氧代-4-(三氟乙酰)-哌啶-1-羧酸叔-丁酯以7mL乙酸稀释,然后向其中加入107mg(1.53mmol)羟胺,接着回流。 [0699] The obtained reference 365mg WO 04/064778 (1.24mmol) 3- oxo-4- (trifluoroacetyl) - piperidine-1-carboxylic acid tert - butyl ester was diluted with 7mL of acetic acid, was added thereto and then 107mg (1.53 mmol) of hydroxylamine, followed by reflux. 回流6小时之后,反应液冷却至室温,减压下去除乙酸。 After reflux for 6 hours, the reaction was cooled to room temperature, acetic acid is removed under reduced pressure. 分离所得的化合物,然后通过prep-TLC纯化,得到45mg标题化合物,收率19%。 The resulting compound was isolated and purified by prep-TLC to give 45mg of the title compound in a yield of 19%.

[0700] 1H NMR(CDCl3)δ4.05(1H,s),3.04-3.02(2H,m),2.70-2.69(2H,m) [0700] 1H NMR (CDCl3) δ4.05 (1H, s), 3.04-3.02 (2H, m), 2.70-2.69 (2H, m)

[0701] 质量(m/e)193(M+1) [0701] mass (m / e) 193 (M + 1)

[0702] 制备45:合成[3-氧代-1-(2-氧代-哌啶-1-基甲基)-3-(3-三氟甲基-4,5-二氢-7H-异噁唑并[3,4-c]吡啶-6-基)-丙基]-1S-氨基甲酸叔-丁酯 [0702] Preparation 45: Synthesis of [3-oxo-1- (2-oxo - piperidin-1-yl) -3- (3-trifluoromethyl-4,5-dihydro -7H- isoxazolo [3,4-c] pyridin-6-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0703] 将11.8mg(0.087mmol)1-羟基苯并三唑和166mg(0.087mmol)EDC依序室温下滴加至下述溶液:制备42获得的20mg(0.067mmol)3S-叔-丁氧基羰基氨基-4-(2-氧代-哌啶-1-基)-丁酸溶解于10mL二甲基甲酰胺形成的溶液。 [0703] A 11.8mg (0.087mmol) 1- hydroxybenzotriazole and 166mg (0.087mmol) of EDC was added dropwise to the solution below room temperature in sequence: Preparation of 42 20mg (0.067mmol) 3S- obtained tert - butoxy benzyloxycarbonylamino-4- (2-oxo - piperidin-1-yl) - butanoic acid was dissolved in 10mL of dimethylformamide was formed. 搅拌10分钟之后,向反应液滴加下述溶液:制备44获得的14mg(0.073mmol)3-三氟甲基-4,5,6,7-四氢-异噁唑[3,4,c]吡啶溶解于3mL二甲基甲酰胺。 After stirring for 10 minutes, the following solution was added to the reaction liquid: 14mg (0.073mmol) obtained in Preparation 44 3-trifluoromethyl-4,5,6,7-tetrahydro - isoxazole [3,4, c ] pyridine was dissolved in 3mL dimethylformamide. 室温下搅拌10分钟之后,向溶液加入0.035mL(0.20mmol)二异丙基乙胺。 After stirring at room temperature for 10 minutes, 0.035mL (0.20mmol) of diisopropylethylamine to the solution. 室温下搅拌12小时之后,反应液以乙酸乙酯稀释,并依序用1N盐酸水溶液和NaCl水溶液洗涤,然后有机层用无水硫酸镁干燥,过滤。 After stirring at room temperature for 12 hours, the reaction was diluted with ethyl acetate, and washed sequentially with 1N aqueous hydrochloric acid and aqueous NaCl solution, the organic layer was dried over anhydrous magnesium sulfate and then filtered. 减压下蒸馏掉滤液,残留物通过prep-TLC分离和纯化,得到23mg标题化合物,收率73%。 The filtrate was distilled off, the residue was separated and purified by prep-TLC, to give 23mg of the title compound in a yield of 73% under reduced pressure.

[0704] 1H NMR(CDCl3)δ5.87-5.86(1H,m),4.86(1H,brs),4.76-4.70(1H,m),4.14(1H,brs),3.81(1H,brs),3.70-3.64(2H,m),3.44-3.30(3H,m),2.85-2.77(2H,m),2.50-2.45(1H,m),2.33-2.32(2H,m),1.83(1H,brs),1.77-1.75(4H,m),1.39(9H,s). [0704] 1H NMR (CDCl3) δ5.87-5.86 (1H, m), 4.86 (1H, brs), 4.76-4.70 (1H, m), 4.14 (1H, brs), 3.81 (1H, brs), 3.70 -3.64 (2H, m), 3.44-3.30 (3H, m), 2.85-2.77 (2H, m), 2.50-2.45 (1H, m), 2.33-2.32 (2H, m), 1.83 (1H, brs) , 1.77-1.75 (4H, m), 1.39 (9H, s).

[0705] 质量(m/e)475(M+1) [0705] mass (m / e) 475 (M + 1)

[0706] 制备46:合成[3-氧代-1-(2-氧代-哌啶-1-基甲基)-3-(3-三氟甲基-1,4,5,7-四氢-吡唑并[3,4-c]吡啶-6-基)-丙基]-1S-氨基甲酸叔-丁酯 [0706] Preparation 46: Synthesis of [3-oxo-1- (2-oxo - piperidin-1-yl) -3- (3-trifluoromethyl-4,5,7-four hydrogen - pyrazolo [3,4-c] pyridin-6-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0707] 除了利用参照WO 04/064778获得的14mg(0.062mmol)3-(三氟甲基)-4,5,6,7-四氢-1H-吡唑并[3,4-c]吡啶盐酸盐和制备43获得的17mg(0.057mmol)3S-叔-丁氧基羰基氨基-4-(2-氧代-哌啶-1-基)-丁酸之外,以制备45的相同方式,获得25mg标题化合物,收率93%。 [0707] In addition to using a reference 14mg (0.062mmol) 3- (trifluoromethyl) -4,5,6,7-tetrahydro -1H- pyrazol obtained and WO 04/064778 [3,4-c] pyridine hydrochloride and 17mg (0.057mmol) obtained in preparation 43 3S- tert - butoxycarbonylamino-4- (2-oxo - piperidin-1-yl) - butanoic acid addition, 45 is prepared in the same manner to give 25mg of the title compound in 93% yield.

[0708] 1H NMR(CDCl3)δ5.99-5.90(1H,m),4.82-4.64(2H,m),4.30-20(1H,m),3.90-3.84(1H,m),3.68-3.66(1H,m),3.64-3.31(5H,m),2.96-2.71(3H,m),2.66-2.56(1H,m),2.41-2.37(2H,m),1.93(1H,brs),1.79(2H,brs),1.39(9H,m) [0708] 1H NMR (CDCl3) δ5.99-5.90 (1H, m), 4.82-4.64 (2H, m), 4.30-20 (1H, m), 3.90-3.84 (1H, m), 3.68-3.66 ( 1H, m), 3.64-3.31 (5H, m), 2.96-2.71 (3H, m), 2.66-2.56 (1H, m), 2.41-2.37 (2H, m), 1.93 (1H, brs), 1.79 ( 2H, brs), 1.39 (9H, m)

[0709] 质量(m/e)474(M+1) [0709] mass (m / e) 474 (M + 1)

[0710] 实施例19:合成1-[2S-氨基-4-氢代-4-(3-三氟甲基-4,5-二氢-7H-异噁唑并[3,4-c]吡啶-6-基)丁基]-哌啶-2-酮 [0710] Example 19: Synthesis of 1- [2S- hydrogen-amino-4-4- (3-trifluoromethyl-4,5-dihydro -7H- isoxazolo [3,4-c] pyridin-6-yl) butyl] - piperidin-2-one

[0711] [0711]

[0712] 除了利用制备45获得的23mg(0.048mmol)[3-氧代-1-(2-氧代-哌啶-1-基甲基)-3-(3-三氟甲基-4,5-二氢-7H-异噁唑并[3,4-c]吡啶-6-基)-丙基]-1S-氨基甲酸叔-丁酯之外,以实施例3的相同方式,获得9.9mg标题化合物,收率50%。 [0712] Besides using 23mg (0.048mmol) obtained in Preparation 45 [3-oxo-1- (2-oxo - piperidin-1-yl) -3- (3-trifluoromethyl-4, 4,5-dihydro -7H- isoxazolo [3,4-c] pyridin-6-yl) - propyl] amino-1S-tert - butyl ester addition, in the same manner as in Example 3, to obtain 9.9 mg of the title compound in 50% yield.

[0713] 1H NMR(CD3OD)δ5.45-5.47(1H,m),3.86-3.68(3H,m),3.45-3.28(4H,m),2.90-2.68(4H,m),2.37-2.34(2H,m),1.89-1.78(5H,m). [0713] 1H NMR (CD3OD) δ5.45-5.47 (1H, m), 3.86-3.68 (3H, m), 3.45-3.28 (4H, m), 2.90-2.68 (4H, m), 2.37-2.34 ( 2H, m), 1.89-1.78 (5H, m).

[0714] 质量(m/e)375(M+1) [0714] mass (m / e) 375 (M + 1)

[0715] 实施例20:合成1-[2S-氨基-4-氧代-4-(3-三氟甲基-1,4,5,7-四氢-吡唑并[3,4-c]吡啶-6-基)-丁基]-哌啶-2-酮 [0715] Example 20: Synthesis of 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-4,5,7-tetrahydro - pyrazolo [3,4-c ] pyridin-6-yl) - butyl] - piperidin-2-one

[0716] [0716]

[0717] 除了利用制备46获得的25mg(0.053mmol)[3-氧代-1-(2-氧代-哌啶-1-基甲基)-3-(3-三氟甲基-1,4,5,7-四氢-吡唑并[3,4-c]吡啶-6-基)-丙基]-1S-氨基甲酸叔-丁酯之外,以实施例3的相同方式,获得8.9mg标题化合物,收率41%。 [0717] Preparation 46 except using the obtained 25mg (0.053 mmol) [3- oxo-1- (2-oxo - piperidin-1-yl) -3- (3-trifluoromethyl-1, 4,5,7-tetrahydro - pyrazolo [3,4-c] pyridin-6-yl) - propyl] amino-1S-tert - butyl ester addition, in the same manner as Example 3 to obtain 8.9mg of the title compound in 41% yield.

[0718] 1H NMR(CD3OD)δ4.84-4.73(1H,m),4.12-3.73(3H,m),3.54-3.37(4H,m),2.30-2.70(4H,m),2.46-2.34(2H,m),1.94-1.80(5H,m) [0718] 1H NMR (CD3OD) δ4.84-4.73 (1H, m), 4.12-3.73 (3H, m), 3.54-3.37 (4H, m), 2.30-2.70 (4H, m), 2.46-2.34 ( 2H, m), 1.94-1.80 (5H, m)

[0719] 质量(m/e)374(M+1) [0719] mass (m / e) 374 (M + 1)

[0720] 制备47:合成3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯 [0720] Preparation 47: Synthesis of 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester

[0721] 将5.0g(25mmol)3-氧代哌啶-1-羧酸叔-丁酯溶解于二甲氧基乙烷,所得溶液冷却至-78℃,然后滴加30mL(30mmol)六甲基二硅氮烷锂(LHMDS,1MTHF溶液),搅拌约1小时,接着滴加3.9mL(33mmol)三氟乙酸乙酯。 [0721] A 5.0g (25mmol) 3- oxo-piperidine-1-carboxylic acid tert - butyl ester was dissolved in dimethoxyethane, and the resulting solution was cooled to -78 deg.] C, and then added dropwise 30mL (30mmol) Rokko yl disilazane lithium (LHMDS, 1M THF solution), stirred for about 1 hour, followed by dropwise addition of 3.9mL (33mmol) of ethyl trifluoroacetate. 搅拌1小时之后,取出干冰/丙酮浴,然后反应液加热至室温继续搅拌约2小时30分钟。 After stirring for 1 hour, remove the dry ice / acetone bath, then the reaction was heated to room temperature and stirring was continued for about 2 hours and 30 minutes. 反应液以饱和氯化铵水溶液洗涤之后,用乙酸乙酯萃取三次。 After the reaction solution was washed with saturated aqueous ammonium chloride, extracted with ethyl acetate three times. 有机层用无水硫酸镁干燥,减压下蒸馏掉溶剂,然后残留物通过柱层析纯化(20∶1二氯甲烷∶甲醇),得到6.0g标题化合物,收率81%。 The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (20:1 methylene chloride: methanol), to give 6.0g of the title compound in 81% yield.

[0722] 1H NMR(CDCl3)δ4.22(2H,br s),3.56(2H,m),2.57(2H,br s),1.49(9H,s) [0722] 1H NMR (CDCl3) δ4.22 (2H, br s), 3.56 (2H, m), 2.57 (2H, br s), 1.49 (9H, s)

[0723] 质量(m/e)296(M+1) [0723] mass (m / e) 296 (M + 1)

[0724] 制备48:合成4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-羧酸叔-丁酯 [0724] Preparation 48: Synthesis of 4-trifluoromethyl-5,8-dihydro--6H- pyrido [3,4-d] pyrimidine-7-carboxylic acid tert - butyl ester

[0725] 将0.52mL甲醇钠(21%wt.乙醇溶液)室温下添加至下述溶液:95mg(1.18mmol)甲脒盐酸盐室温下溶解于2mL无水乙醇形成的溶液。 (Ethanol was 21% wt) [0725] 0.52mL added at room temperature to a solution of sodium methoxide following: 95mg (1.18mmol) was dissolved in 2mL of anhydrous ethanol was formed at room temperature formamidine hydrochloride. 室温搅拌10分钟之后,向所得溶液加入下述溶液:232mg(0.786mmol)3-氧代-4-(三氟乙酰)-哌啶-1-羧酸叔-丁酯(制备47的产物)用2mL无水乙醇稀释。 After stirring at room temperature for 10 minutes, the following solution was added to the resulting solution: 232mg (0.786mmol) 3- oxo-4- (trifluoroacetyl) - piperidine-1-carboxylic acid tert - butyl ester (the product of Preparation 47) using 2mL ethanol diluted. 其后,溶液温度升高至80℃,接着搅拌约18小时。 Thereafter, the solution temperature was raised to 80 ℃, followed by stirring for about 18 hours. 冷却至室温后,减压下去除乙醇,反应液以乙酸乙酯稀释,然后依次用NaCl水溶液洗涤。 After cooling to room temperature, ethanol was removed under reduced pressure, the reaction was diluted with ethyl acetate, then successively washed with aqueous NaCl solution. 有机层用无水硫酸镁干燥,过滤。 The organic layer was dried over anhydrous magnesium sulfate, and filtered. 减压下蒸馏掉滤液,然后残留物通过prep-TLC分离和纯化(乙酸乙酯20%正-己烷的溶剂溶液),得到30mg标题化合物,收率13%。 The filtrate was distilled off under reduced pressure, and the residue was purified by prep-TLC was separated and purified (20% ethyl acetate in n - hexane in solvent), to give 30mg of the title compound in 13% yield.

[0726] 1H NMR(CDCl3)δ9.11(1H,s),4.73(2H,s),3.72(2H,t,J=5.5Hz),3.02(2H,br s),1.48(9H,s) [0726] 1H NMR (CDCl3) δ9.11 (1H, s), 4.73 (2H, s), 3.72 (2H, t, J = 5.5Hz), 3.02 (2H, br s), 1.48 (9H, s)

[0727] 质量(m/e)248(M+1-叔丁基) [0727] mass (m / e) 248 (M + 1- t-butyl)

[0728] 制备49:合成4-三氟甲基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0728] Preparation 49: Synthesis of 4-trifluoromethyl-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0729] 制备48获得的30mg(0.099mmol)4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-羧酸叔-丁酯室温下添加至1.8mL 3N HCl-乙酸乙酯溶液。 30mg [0729] obtained in Preparation 48 (0.099mmol) 4- trifluoromethyl-5,8-dihydro--6H- pyrido [3,4-d] pyrimidine-7-carboxylic acid tert - butyl ester at room temperature was added to 1.8mL 3N HCl- ethyl acetate solution. 室温搅拌10分钟之后,去除过量HCl-乙酸乙酯溶液,浓缩后得到标题化合物。 After stirring at room temperature for 10 minutes, removing excess HCl- ethyl acetate solution was concentrated to give the title compound. 该化合物用于下次反应,无需任何进一步纯化。 The compound for the next reaction without any further purification.

[0730] 1H NMR(CD3OD)δ4.44(2H,s),3.55-3.52(2H,m),3.23-3.20(2H,m) [0730] 1H NMR (CD3OD) δ4.44 (2H, s), 3.55-3.52 (2H, m), 3.23-3.20 (2H, m)

[0731] 质量(m/e)204(M+1) [0731] mass (m / e) 204 (M + 1)

[0732] 制备50:合成(3S)-叔-丁氧基羰基氨基-4-[(5R)-甲基-2-氧代-哌啶-1-基]-丁酸叔-丁酯 [0732] Preparation 50: Synthesis of (3S) - tert - butoxycarbonyl-amino -4 - [(5R) - 2-oxo - piperidin-1-yl] - butyric acid tert - butyl ester

[0733] 除了利用363mg(1.33mmol)3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯(制备41的产物)和制备7获得的220mg(1.21mmol)(R)-5-氨基-4-甲基-戊酸甲酯盐酸盐之外,以制备42的相同方式,获得359mg标题化合物,收率73%。 [0733] ​​Besides using 363mg (1.33mmol) 3S- tert - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester 220 mg of (the product of Preparation 41) and obtained in Preparation 7 (1.21mmol) (R) 5-amino-4-methyl - pentanoic acid methyl ester hydrochloride addition, in the same manner as in preparation 42, to obtain 359mg of the title compound in 73% yield.

[0734] 1H NMR(CDCl3)δ5.40-5.31(1H,m),4.17(1H,br s),3.89-3.80(1H,m),3.25-3.03(3H,m),2.58-2.29(2H,m),1.98-1.88(1H,m),1.84-1.80(1H,m),1.46(9H,s),1.42(9H,s),1.01(3H,d,J=6.4Hz) [0734] 1H NMR (CDCl3) δ5.40-5.31 (1H, m), 4.17 (1H, br s), 3.89-3.80 (1H, m), 3.25-3.03 (3H, m), 2.58-2.29 (2H , m), 1.98-1.88 (1H, m), 1.84-1.80 (1H, m), 1.46 (9H, s), 1.42 (9H, s), 1.01 (3H, d, J = 6.4Hz)

[0735] 质量(m/e)371(M+1) [0735] mass (m / e) 371 (M + 1)

[0736] 制备51:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5R-甲基-2-氧代-哌啶-1-基)-丁酸 [0736] Preparation 51: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5R--2-oxo - piperidin-1-yl) - butanoic acid

[0737] 除了利用制备50获得的(3S)-叔-丁氧基羰基氨基-4-[(5R)-甲基-2-氧代-哌啶-1-基]-丁酸叔-丁酯359mg(0.97mmol)之外,以制备43的相同方式,获得116mg标题化合物,收率38%。 [0737] In addition to (3S) prepared using the obtained 50 - t - butoxycarbonyl-amino -4 - [(5R) - 2-oxo - piperidin-1-yl] - butyric acid tert - butyl ester addition to 359mg (0.97mmol), in the same manner as in preparation 43, to obtain 116mg of the title compound in 38% yield.

[0738] 1H NMR(CDCl3)δ8.50(1H,br s),5.75-5.73(1H,m),4.16(1H,brs),3.76-3.54(2H,m),3.44-3.34(1H,m),3.16-2.97(1H,m),2.59-2.38(4H,m),1.98(1H,br s),1.86-1.84(1H,m),1.45(9H,s),1.04(3H,d,J=6.8Hz) [0738] 1H NMR (CDCl3) δ8.50 (1H, br s), 5.75-5.73 (1H, m), 4.16 (1H, brs), 3.76-3.54 (2H, m), 3.44-3.34 (1H, m ), 3.16-2.97 (1H, m), 2.59-2.38 (4H, m), 1.98 (1H, br s), 1.86-1.84 (1H, m), 1.45 (9H, s), 1.04 (3H, d, J = 6.8Hz)

[0739] 质量(m/e)315(M+1) [0739] mass (m / e) 315 (M + 1)

[0740] 制备52:合成[1-(5R-甲基-2-氧代-哌啶-1-基甲基)-3-氧代-3-(4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-基)-丙基]-1S-氨基甲酸叔-丁酯 [0740] Preparation 52: Synthesis of [1- (5R--2-oxo - piperidin-1-ylmethyl) -3-oxo-3- (4-trifluoromethyl-5,8 -6H- dihydro-pyrido [3,4-d] pyrimidin-7-yl) - propyl] 1S-carbamic acid tert - butyl ester

[0741] 除了利用制备51获得的34.1mg(0.108mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-甲基-2-氧代-哌啶-1-基]-丁酸和制备49获得的26mg(0.109mmol)4-三氟甲基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得35mg标题化合物,收率65%。 [0741] Preparation 51 except for using the obtained 34.1mg (0.108mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) - 2-oxo - piperidine 1-yl] - outside (0.109mmol) 4- trifluoromethyl-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride obtained in preparation 49 and butyric acid 26mg in the same manner as in preparation 45, to obtain 35mg of the title compound in 65% yield.

[0742] 1H NMR(CDCl3)δ9.15(1H,s),5.95-5.88(1H,m),4.95-4.70(2H,m),4.15(1H,br s),3.92-3.89(1H,m),3.86-3.80(1H,m),3.57-3.55(1H,m),3.36(1H,br s),3.09-3.00(3H,m),2.89-2.81(1H,m),2.54-2.30(3H,m),1.94(1H,br s),1.81(1H,br s),1.64(2H,br s),1.42-1.40(9H,m),1.02-1.00(3H,m) [0742] 1H NMR (CDCl3) δ9.15 (1H, s), 5.95-5.88 (1H, m), 4.95-4.70 (2H, m), 4.15 (1H, br s), 3.92-3.89 (1H, m ), 3.86-3.80 (1H, m), 3.57-3.55 (1H, m), 3.36 (1H, br s), 3.09-3.00 (3H, m), 2.89-2.81 (1H, m), 2.54-2.30 ( 3H, m), 1.94 (1H, br s), 1.81 (1H, br s), 1.64 (2H, br s), 1.42-1.40 (9H, m), 1.02-1.00 (3H, m)

[0743] 质量(m/e)500(M+1) [0743] mass (m / e) 500 (M + 1)

[0744] 实施例21:合成1-[2S-氨基-4-氧代-4-(4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-基)-丁基]-5R-甲基-1-哌啶-2-酮 [0744] Example 21: Synthesis of 1- [2S- amino-4-oxo-4- (4-trifluoromethyl-5,8-dihydro--6H- pyrido [3,4-d] pyrimidine - 7- yl) - butyl] -1-5R-methyl-2-one

[0745] [0745]

[0746] 除了利用制备52获得的35mg(0.053mmol)1-(5R-甲基-2-氧代-哌啶-1-基甲基)-3-氧代-3-(4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-基)-丙基]-1S-氨基甲酸叔-丁酯之外,以实施例3的相同方式,获得14.5mg标题化合物,收率51%。 [0746] Preparation 52 except for using the obtained 35mg (0.053mmol) 1- (5R--2-oxo - piperidin-1-ylmethyl) -3-oxo-3- (4- trifluoromethanesulfonyloxy -6H--5,8-dihydro-pyrido [3,4-d] pyrimidin-7-yl) - propyl] amino-1S-tert - butyl ester addition, in the same manner as in Example 3, 14.5mg title compound was obtained in 51% yield.

[0747] 1H NMR(CD3OD)δ9.15-9.14(1H,m),9.95(1H,t,J=6.0Hz),3.90-3.86(1H,m),3.80-3.77(1H,m),3.71-3.65(1H,m),3.58-3.53(1H,m),3.48-3.37(3H,m),3.18-3.07(3H,m),2.94-2.87(1H,m),2.80-2.75(1H,m),2.58-2.34(2H,m),2.05-2.03(1H,m),1.89-1.85(1H,m),1.60-1.47(1H,m),1.06(3H,d,J=2.8Hz) [0747] 1H NMR (CD3OD) δ9.15-9.14 (1H, m), 9.95 (1H, t, J = 6.0Hz), 3.90-3.86 (1H, m), 3.80-3.77 (1H, m), 3.71 -3.65 (1H, m), 3.58-3.53 (1H, m), 3.48-3.37 (3H, m), 3.18-3.07 (3H, m), 2.94-2.87 (1H, m), 2.80-2.75 (1H, m), 2.58-2.34 (2H, m), 2.05-2.03 (1H, m), 1.89-1.85 (1H, m), 1.60-1.47 (1H, m), 1.06 (3H, d, J = 2.8Hz)

[0748] 质量(m/e)374(M+1) [0748] mass (m / e) 374 (M + 1)

[0749] 制备53:合成(S)-(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐 [0749] Preparation 53: Synthesis of (S) - (2- amino-l - methyl-ethoxy) - acetate hydrochloride

[0750] (1)合成(S)-(2-羟基-丙基)-氨基甲酸叔-丁酯 [0750] (1) Synthesis of (S) - (2- hydroxy - propyl) - carbamic acid tert - butyl ester

[0751] 将500mg(6.65mmol)(S)-1-氨基-丙烷-2-醇溶解于20mL甲醇和5mL水,然后向其中加入1.85g(8.45mmol)二碳酸二-叔-丁酯,接着搅拌3小时。 [0751] A 500mg (6.65mmol) (S) -1- amino - 2-ol was dissolved in 20mL of methanol and 5mL of water, and thereto was added 1.85g (8.45mmol) of di - tert - butyl ester, followed by for 3 hours. 其中加入200mL乙酸乙酯,反应液以水洗涤。 200mL of ethyl acetate was added thereto, the reaction solution was washed with water. 有机层用无水硫酸镁干燥,减压下蒸馏掉溶剂,然后残留物通过柱层析纯化,得到802g(4.57mmol)标题化合物,收率68%。 The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, then the residue was purified by column chromatography, to give 802g (4.57mmol) of the title compound in 68% yield.

[0752] NMR:1H-NMR(CDCl3)δ4.91(1H,brs),3.95~3.85(1H,m),3.30~3.22(1H,m),3.04~2.97(1H,m),2.31(1H,brs),1.45(9H,s),1.18(3H,d,J=8Hz) [0752] NMR: 1H-NMR (CDCl3) δ4.91 (1H, brs), 3.95 ~ 3.85 (1H, m), 3.30 ~ 3.22 (1H, m), 3.04 ~ 2.97 (1H, m), 2.31 (1H , brs), 1.45 (9H, s), 1.18 (3H, d, J = 8Hz)

[0753] 质量(EI)176(M++1) [0753] mass (EI) 176 (M ++ 1)

[0754] (2)合成(S)-(2-叔-丁氧基羰基氨基-1-甲基-乙氧基)-乙酸乙酯 [0754] (2) Synthesis of (S) - (2- tert - butoxycarbonylamino-1-methyl - ethoxy) - ethyl

[0755] 将1.16g(6.61mmol)(S)-(2-羟基-丙基)-氨基甲酸叔-丁酯溶解于20mL二氯乙烷,然后向其中加入0.66mL(9.84mmol)重氮乙酸乙酯。 [0755] A 1.16g (6.61mmol) (S) - (2- hydroxy - propyl) - carbamic acid tert - butyl ester was dissolved in 20mL of dichloroethane, and then thereto was added 0.66mL (9.84mmol) diazoacetate ethyl ester. 向其中滴加57mg(0.12mmol)乙酸铑,然后加热至80℃2小时。 Rhodium acetate was dropwise added thereto 57mg (0.12mmol), then heated to 80 ℃ 2 hours. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到1.2g(4.59mmol)标题化合物,收率69%。 The solvent was distilled off, the residue was purified by column chromatography to give 1.2g (4.59mmol) of the title compound in a yield of 69% under reduced pressure.

[0756] NMR:1H-NMR(CDCl3)δ5.39(1H,s),4.23(2H,q,J=8Hz),4.09(1H,d,J=16Hz),4.00(1H,d,J=16Hz),3.60~3.35(1H,m),3.35~3.15(1H,m),3.10~3.04(1H,m),1.46(9H,s),1.31(3H,t,J=4Hz),1.16(3H,d,J=4Hz) [0756] NMR: 1H-NMR (CDCl3) δ5.39 (1H, s), 4.23 (2H, q, J = 8Hz), 4.09 (1H, d, J = 16Hz), 4.00 (1H, d, J = 16Hz), 3.60 ~ 3.35 (1H, m), 3.35 ~ 3.15 (1H, m), 3.10 ~ 3.04 (1H, m), 1.46 (9H, s), 1.31 (3H, t, J = 4Hz), 1.16 ( 3H, d, J = 4Hz)

[0757] 质量(EI)262(M++1) [0757] mass (EI) 262 (M ++ 1)

[0758] (3)合成(S)-(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐 [0758] (3) Synthesis of (S) - (2- amino-l - methyl-ethoxy) - acetate hydrochloride

[0759] 将1.2g(4.59mmol)(S)-(2-叔-丁氧基羰基氨基-1-甲基-乙氧基)-乙酸乙酯溶解于20mL以盐酸气体饱和的乙酸乙酯,接着室温下搅拌3小时。 [0759] A 1.2g (4.59mmol) (S) - (2- tert - butoxycarbonylamino-1-methyl-ethoxy) - - was dissolved in 20mL ethyl acetate to ethyl acetate saturated with hydrochloric acid gas, followed by stirring at room temperature for 3 hours. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到699mg(3.49mmol)标题化合物,收率76%。 The solvent was distilled off under reduced pressure, the residue was purified by column chromatography to give 699mg (3.49mmol) of the title compound, yield 76%.

[0760] NMR:1H-NMR(CD3OD)δ5.05(2H,s),4.32~4.19(4H,m),3.88~3.83(1H,m),3.16~3.12(1H,m),2.96~2.90(1H,m),1.32(3H,t,J=7.2Hz),1.25(3H,d,J=6Hz) [0760] NMR: 1H-NMR (CD3OD) δ5.05 (2H, s), 4.32 ~ 4.19 (4H, m), 3.88 ~ 3.83 (1H, m), 3.16 ~ 3.12 (1H, m), 2.96 ~ 2.90 (1H, m), 1.32 (3H, t, J = 7.2Hz), 1.25 (3H, d, J = 6Hz)

[0761] 质量(EI)200(M++1) [0761] mass (EI) 200 (M ++ 1)

[0762] 制备54:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]-丁酸叔-丁酯 [0762] Preparation 54: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-morpholin-4-yl] - butoxy acid tert - butyl ester

[0763] 以制备50的相同方式,将与制备41相同的方式获得的3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯与制备53获得的457mg(2.31mmol)(S)-(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐反应,得到767mg标题化合物,总收率81%。 [0763] 3S- tert prepared in the same manner as 50, obtained in the same manner as Preparation 41 - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester obtained in Preparation 53 and 457mg (2.31mmol) (S) - (2- amino-l - methyl-ethoxy) - acetate hydrochloride to give the title compound 767mg, 81% overall yield.

[0764] 1H NMR(CDCl3)δ5.22(1H,d,J=8.5Hz),4.17(2H,Abq,J=18Hz),3.87(1H,m),3.66(1H,dd,J=13.5,8.5Hz),3.41(1H,t,J=11.0Hz),3.31(1H,dd,J=13.55.0Hz),2.90(1H,dd,J=12.0,2.5Hz),2.52(1H,dd,J=16.0,5.0Hz),2.41(1H,dd,J=16.0,6,5Hz),1.44(9H,s),1.41(9H,s),1.25(3H,d,J=6.0Hz) [0764] 1H NMR (CDCl3) δ5.22 (1H, d, J = 8.5Hz), 4.17 (2H, Abq, J = 18Hz), 3.87 (1H, m), 3.66 (1H, dd, J = 13.5, 8.5Hz), 3.41 (1H, t, J = 11.0Hz), 3.31 (1H, dd, J = 13.55.0Hz), 2.90 (1H, dd, J = 12.0,2.5Hz), 2.52 (1H, dd, J = 16.0,5.0Hz), 2.41 (1H, dd, J = 16.0,6,5Hz), 1.44 (9H, s), 1.41 (9H, s), 1.25 (3H, d, J = 6.0Hz)

[0765] 质量(m/e)395(M+Na) [0765] mass (m / e) 395 (M + Na)

[0766] 制备55:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]-丁酸 [0766] Preparation 55: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-morpholin-4-yl] - butoxy acid

[0767] 除了利用制备54获得的767mg(2.06mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]-丁酸叔-丁酯之外,以制备43的相同方式,获得580mg标题化合物,总收率89%。 [0767] Preparation 54 except for using the obtained 767mg (2.06mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-morpholine 4-yl] - butyric acid tert - butyl ester addition, in the same manner as in preparation 43 to give the title compound 580mg, 89% overall yield.

[0768] 1H NMR(CD3OD)δ4.23(1H,m),4.11(2H,s),3.88(1H,m),3.50(1H,dd,J=13.58.5Hz),3.39(2H,m),2.50(1H,dd,J=16,6Hz),2.44(1H,dd,J=16,7Hz),1.41(9H,s),1.22(3H,d,J=7Hz) [0768] 1H NMR (CD3OD) δ4.23 (1H, m), 4.11 (2H, s), 3.88 (1H, m), 3.50 (1H, dd, J = 13.58.5Hz), 3.39 (2H, m) , 2.50 (1H, dd, J = 16,6Hz), 2.44 (1H, dd, J = 16,7Hz), 1.41 (9H, s), 1.22 (3H, d, J = 7Hz)

[0769] 质量(m/e)317(M+1) [0769] mass (m / e) 317 (M + 1)

[0770] 制备56:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸叔-丁酯 [0770] Preparation 56: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin-1-yl) - butyric acid tert - butyl

[0771] 除了利用3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯(制备41的产物)和制备12获得的471mg(2.31mmol)5-氨基-4,4-二氟戊酸甲酯盐酸盐之外,以制备42的相同方式,获得900mg标题化合物,收率90%。 [0771] In addition to using 3S- tert - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester 471 mg (the product of Preparation 41) and obtained in Preparation 12 (2.31mmol) 5- amino-4,4 addition-difluoropentanoate hydrochloride, in the same manner as in preparation 42, to obtain 900mg of the title compound in 90% yield.

[0772] 1H NMR(CDCl3)δ5.19(1H,d,J=8.0Hz),3.5-4.0(4H,m),3.20(1H,dd,J=14,4Hz),2.6(2H,m),2.5(1H,dd,J=16,4Hz),2.4(1H,dd,J=16,8Hz),2.2-2.3(2H,m),1.46(9H,s),1.42(9H,s) [0772] 1H NMR (CDCl3) δ5.19 (1H, d, J = 8.0Hz), 3.5-4.0 (4H, m), 3.20 (1H, dd, J = 14,4Hz), 2.6 (2H, m) , 2.5 (1H, dd, J = 16,4Hz), 2.4 (1H, dd, J = 16,8Hz), 2.2-2.3 (2H, m), 1.46 (9H, s), 1.42 (9H, s)

[0773] 质量(m/e)393(M+1) [0773] mass (m / e) 393 (M + 1)

[0774] 制备57:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸 [0774] Preparation 57: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin-1-yl) - butanoic acid

[0775] 除了利用制备56获得的900mg(2.29mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸叔-丁酯之外,以制备43的相同方式,获得298mg标题化合物,收率39%。 [0775] Preparation 56 except that obtained using 900mg (2.29mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) - butanoic acid tert - butyl ester addition, in the same manner as in preparation 43, to obtain 298mg of the title compound in 39% yield.

[0776] 1H NMR(CD3OD)δ4.19(1H,m),3.87(1H,br q,J=13Hz),3.7(1H,br q,J=13Hz),3.52(1H,dd,J=14,9Hz),3.37(1H,m),2.4-2.6(4H,m),2.2-2.3(2H,m),1.40(9H,s) [0776] 1H NMR (CD3OD) δ4.19 (1H, m), 3.87 (1H, br q, J = 13Hz), 3.7 (1H, br q, J = 13Hz), 3.52 (1H, dd, J = 14 , 9Hz), 3.37 (1H, m), 2.4-2.6 (4H, m), 2.2-2.3 (2H, m), 1.40 (9H, s)

[0777] 质量(m/e)337(M+1) [0777] mass (m / e) 337 (M + 1)

[0778] 制备58:合成2-(4-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0778] Preparation 58: Synthesis of 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0779] (1)合成4-氟苯脒 [0779] (1) Synthesis of 4-fluorophenyl amidines

[0780] 将4.12mL(8.24mmol)三甲基铝(2.0M甲苯溶液)室温下滴加至10mL含有441mg(8.24mmol)氯化铵的甲苯中。 [0780] The lower 4.12mL (8.24mmol) of trimethylaluminum (2.0M solution in toluene) was added dropwise to a room temperature and 10mL containing 441mg (8.24mmol) of ammonium chloride in toluene. 搅拌1.5小时之后,向其中加入1g(8.25mmol)4-氟苯腈,所得混合物加热至85℃9小时。 After stirring for 1.5 hours, and thereto was added 1g (8.25mmol) 4- fluorobenzonitrile, the resulting mixture was heated to 85 ℃ 9 hours. 反应完成之后,反应液冷却,倾倒至100mL含有500g硅胶的氯仿,过滤。 After completion of the reaction, the reaction solution was cooled, poured into 100mL of chloroform containing 500g of silica gel, and filtered. 残留物以100mL甲醇洗涤,蒸馏得到821mg(5.9mmol)标题化合物,收率71%。 The residue was washed with 100mL of methanol was distilled to give 821mg (5.9mmol) of the title compound in 71% yield.

[0781] NMR:1H-NMR(DMSO d6)δ9.44(1H,brs),9.25(1H,brs),7.96~7.92(2H,m),7.52~7.31(2H,m) [0781] NMR: 1H-NMR (DMSO d6) δ9.44 (1H, brs), 9.25 (1H, brs), 7.96 ~ 7.92 (2H, m), 7.52 ~ 7.31 (2H, m)

[0782] 质量(EI)139(M++1) [0782] mass (EI) 139 (M ++ 1)

[0783] (2)合成2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [0783] (2) Synthesis of 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate tert - butyl ester

[0784] 以制备48的相同方式,将制备47获得的500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的351m(2.54mmol)4-氟苯脒反应,得到108mg标题化合物,收率16%。 [0784] In the same manner as in Preparation 48, prepared 47 500mg (1.69mmol) 3- obtained oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester, and the above step (1) to obtain the 351m (2.54mmol) 4- fluorophenyl amidine to give the title compound 108mg, 16% yield.

[0785] 1H NMR(CDCl3)δ8.47(2H,m),7.16(2H,t,J=8.5Hz),4.76(2H,s),3.74(2H,t,J=6.0Hz),3.02(2H,br s),1.51(9H,s) [0785] 1H NMR (CDCl3) δ8.47 (2H, m), 7.16 (2H, t, J = 8.5Hz), 4.76 (2H, s), 3.74 (2H, t, J = 6.0Hz), 3.02 ( 2H, br s), 1.51 (9H, s)

[0786] 质量(m/e)398(M+1) [0786] mass (m / e) 398 (M + 1)

[0787] (3)合成2-(4-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0787] (3) Synthesis of 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0788] 将上述步骤(2)获得的108mg(0.306mmol)2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯室温下加入到7.5mL 4N HCl/1,4-二噁烷溶液。 [0788] The above step (2) obtained 108mg (0.306mmol) 2- (4- fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester at room temperature was added to 7.5mL 4N HCl / 1,4- dioxane. 室温搅拌25分钟之后,去除过量HCl/1,4-二噁烷溶液,所得溶液浓缩,得到69mg标题化合物。 After stirring at room temperature for 25 minutes to remove excess HCl / 1,4- dioxane, the resulting solution was concentrated, to give 69mg of the title compound. 该化合物用于下次反应,无需任何进一步纯化。 The compound for the next reaction without any further purification.

[0789] 1H NMR(CD3OD)δ8.54(2H,m),7.29(2H,t,J=10.0Hz),4.60(2H,s),3.67(2H,t,J=6.0Hz),剩余两个质子预期隐藏在3.3ppm的CD3OD中。 [0789] 1H NMR (CD3OD) δ8.54 (2H, m), 7.29 (2H, t, J = 10.0Hz), 4.60 (2H, s), 3.67 (2H, t, J = 6.0Hz), the remaining two protons at 3.3ppm of hidden expected in CD3OD.

[0790] 质量(m/e)298(M+1) [0790] mass (m / e) 298 (M + 1)

[0791] 制备59:合成2-(3,4-二氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0791] Preparation 59: Synthesis of 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine salt salt

[0792] (1)合成3,4-二氟苯脒 [0792] (1) Synthesis of 3,4-difluorophenyl amidine

[0793] 将3.6mL(7.2mmol)三甲基铝(2.0M甲苯溶液)室温下滴加至10mL含有384mg(7.17mmol)氯化铵的甲苯。 [0793] A 3.6mL (7.2mmol) under trimethylaluminum (2.0M solution in toluene) was added dropwise to a room temperature and 10mL of toluene containing 384mg (7.17mmol) of ammonium chloride. 搅拌1.5小时之后,其中加入1g(7.1mmol)3,4-二氟苯腈,所得混合物加热至85℃9小时。 After stirring for 1.5 hours, was added 1g (7.1mmol) 3,4- difluorobenzonitrile, the resulting mixture was heated to 85 ℃ 9 hours. 反应完成之后,反应液倾倒至100mL含有200g硅胶的氯仿,过滤。 After completion of the reaction, the reaction solution was poured into 100mL of chloroform containing 200g of silica gel, and filtered. 残留物以200mL甲醇洗涤,蒸馏得到370mg(2.36mmol)标题化合物,收率33%。 The residue was washed with 200mL of methanol was distilled to give 370mg (2.36mmol) of the title compound in 33% yield.

[0794] NMR:1H-NMR(CD3OD)δ7.87~7.82(1H,m),7.72~7.70(1H,m),7.63~7.55(1H,m) [0794] NMR: 1H-NMR (CD3OD) δ7.87 ~ 7.82 (1H, m), 7.72 ~ 7.70 (1H, m), 7.63 ~ 7.55 (1H, m)

[0795] 质量(EI)157(M++1) [0795] mass (EI) 157 (M ++ 1)

[0796] (2)合成2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [0796] (2) Synthesis of 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[0797] 除了利用制备47获得的380mg(1.28mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述(1)获得的300mg(1.92mmol)3,4-二氟苯脒之外,以制备58-(2)的相同方式,获得25mg标题化合物,收率4.7%。 [0797] Preparation 47 except using the obtained 380mg (1.28mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester and 300 mg of the above (1) obtained in (1.92mmol) 3 addition, 2,4-difluorophenyl amidino, was prepared in the same manner as 58- (2), to obtain 25mg of the title compound in a yield of 4.7%.

[0798] 1H NMR(CDCl3)δ8.3(2H,m),7.25(1H,m),4.76(2H,s),3.75(2H,t,J=6.0Hz),3.03(2H,br s),1.51(9H,s) [0798] 1H NMR (CDCl3) δ8.3 (2H, m), 7.25 (1H, m), 4.76 (2H, s), 3.75 (2H, t, J = 6.0Hz), 3.03 (2H, br s) , 1.51 (9H, s)

[0799] 质量(m/e)416(M+1) [0799] mass (m / e) 416 (M + 1)

[0800] (3)合成2-(3,4-二氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0800] (3) Synthesis of 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine salt salt

[0801] 除了利用上述步骤(2)获得的25mg(0.62mmol)2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备59(3)的相同方式,获得14mg标题化合物,收率74%。 [0801] 25mg except for using the above-described step (2) obtained in (0.62mmol) 2- (3,4- difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester addition, the same manner as in preparation 59 (3), to obtain 14mg of the title compound in 74% yield.

[0802] 1H NMR(CD3OD)δ8.36(2H,m),7.48(1H,m),4.60(2H,s),3.66(2H,t,J=7.5Hz),3.12(2H,m) [0802] 1H NMR (CD3OD) δ8.36 (2H, m), 7.48 (1H, m), 4.60 (2H, s), 3.66 (2H, t, J = 7.5Hz), 3.12 (2H, m)

[0803] 质量(m/e)316(M+1) [0803] mass (m / e) 316 (M + 1)

[0804] 制备60:合成2-(3-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0804] Preparation 60: Synthesis of 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0805] (1)合成3-氟苯脒 [0805] (1) Synthesis of 3-fluorophenyl amidines

[0806] 将4.12mL(8.24mmol)三甲基铝(2.0M甲苯溶液)室温下添加至10mL含有441mg(8.24mmol)氯化铵的甲苯。 [0806] Add the 4.12mL (8.24mmol) of trimethylaluminum (2.0M solution in toluene) at room temperature to 10mL of toluene containing 441mg (8.24mmol) of ammonium chloride. 搅拌1.5小时之后,其中加入2g(28.9mmol)异丁腈,所得混合物加热至85℃9小时。 After stirring for 1.5 hours, which was added 2g (28.9mmol) isobutyronitrile, the resulting mixture was heated to 85 ℃ 9 hours. 反应完成之后,反应液倾倒至200mL含有200g硅胶的氯仿,过滤。 After completion of the reaction, the reaction solution was poured into 200mL of chloroform containing 200g of silica gel, and filtered. 残留物以100mL甲醇洗涤,蒸馏得到731mg(5.29mmol)标题化合物,收率64%。 The residue was washed with 100mL of methanol was distilled to give 731mg (5.29mmol) of the title compound in 64% yield.

[0807] NMR:1H-NMR(CD3OD)δ7.71~7.44(4H,m) [0807] NMR: 1H-NMR (CD3OD) δ7.71 ~ 7.44 (4H, m)

[0808] 质量(EI)139(M++1) [0808] mass (EI) 139 (M ++ 1)

[0809] (2)合成2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [0809] (2) Synthesis of 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate tert - butyl ester

[0810] 除了利用制备47获得的600mg(2.03mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的421mg(3.05mmol)3-氟苯脒之外,以制备61-58(2)的相同方式,获得159mg标题化合物,收率20%。 [0810] Besides using 600mg (2.03mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation 47 - 421mg (3.05mmol) butyl and said step (1) obtained in 3-fluorophenyl addition amidine, 61-58 was prepared in the same manner as (2), to obtain 159mg of the title compound in 20% yield.

[0811] 1H NMR(CDCl3)δ8.25(1H,d,J=8.0Hz),8.15(1H,m),7.45(1H,m),7.18(1H,m),4.78(2H,s),3.75(2H,t,J=6.0Hz),3.13(2H,br s),1.52(9H,s) [0811] 1H NMR (CDCl3) δ8.25 (1H, d, J = 8.0Hz), 8.15 (1H, m), 7.45 (1H, m), 7.18 (1H, m), 4.78 (2H, s), 3.75 (2H, t, J = 6.0Hz), 3.13 (2H, br s), 1.52 (9H, s)

[0812] 质量(m/e)398(M+1) [0812] mass (m / e) 398 (M + 1)

[0813] (3)合成2-(3-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0813] (3) Synthesis of 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0814] 除了利用上述步骤(2)获得的159mg(0.62mmol)2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备58(3)的相同方式,获得88mg标题化合物,收率67%。 [0814] In addition to the above steps (2) 159mg (0.62mmol) of 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as preparation 58 (3), to obtain 88mg of the title compound in 67% yield.

[0815] 1H NMR(CD3OD)δ8.33(1H,m),8.17(1H,m),7.58(1H,m),7.34(1H,m),4.62(2H,s),3.67(2H,t,J=6.5Hz),3.35(2H,m) [0815] 1H NMR (CD3OD) δ8.33 (1H, m), 8.17 (1H, m), 7.58 (1H, m), 7.34 (1H, m), 4.62 (2H, s), 3.67 (2H, t , J = 6.5Hz), 3.35 (2H, m)

[0816] 质量(m/e)298(M+1) [0816] mass (m / e) 298 (M + 1)

[0817] 制备61:合成2-环丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0817] Preparation 61: Synthesis of 2-cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0818] (1)合成2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [0818] (1) Synthesis of 2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[0819] 1.27g甲醇钠(21%wt.乙醇溶液)室温下添加至500mg(4.13mmol)环丙烷脒盐酸盐溶解于50mL异丙醇形成的溶液。 [0819] 1.27g of sodium methoxide (21% wt. Ethanol solution) at room temperature was added to 500mg (4.13mmol) cyclopropane hydrochloride was dissolved in 50mL of isopropyl alcohol. 搅拌30分钟之后,进行浓缩和过滤,向其中加入制备47获得的940mg(3.17mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯,接着加入BF3·OEt2 12μl(3%催化量)。 After stirring for 30 minutes, filtered and concentrated, 940mg (3.17mmol) 3- oxo-47 obtained was prepared to which was added 4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester, followed by addition of BF3 · OEt2 12μl (3% catalyst amount). 所得溶液加热至80℃,接着搅拌19小时。 The resulting solution was heated to 80 ℃, followed by stirring for 19 hours. 冷却至室温后,减压下去除异丙醇。 After cooling to room temperature, isopropanol was removed under reduced pressure. 残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到400mg标题化合物,收率37%。 The residue was purified by column chromatography (10:1 hexanes: ethyl acetate) to give 400mg of the title compound in 37% yield.

[0820] 1H NMR(CDCl3)δ4.62(2H,s),3.68(2H,t,J=5.5Hz),2.93(2H,brs),2.25(1H,m),1.49(9H,s),1.1-1.2(4H,m) [0820] 1H NMR (CDCl3) δ4.62 (2H, s), 3.68 (2H, t, J = 5.5Hz), 2.93 (2H, brs), 2.25 (1H, m), 1.49 (9H, s), 1.1-1.2 (4H, m)

[0821] 质量(m/e)344(M+1) [0821] mass (m / e) 344 (M + 1)

[0822] (2)合成2-环丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0822] (2) Synthesis of 2-cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0823] 除了利用上述步骤(1)获得的400mg(1.16mmol)2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备58-(3)的相同方式,获得264mg标题化合物,收率81%。 [0823] 400mg except for using the above-described step (1) obtained in (1.16mmol) 2- cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as the preparation of 58- (3), to obtain 264mg of the title compound in 81% yield.

[0824] 1H NMR(CD3OD)δ4.40(2H,s),3.56(2H,t,J=6.5Hz),3.20(2H,t,J=6.5Hz),2.29(1H,m),1.20(4H,m) [0824] 1H NMR (CD3OD) δ4.40 (2H, s), 3.56 (2H, t, J = 6.5Hz), 3.20 (2H, t, J = 6.5Hz), 2.29 (1H, m), 1.20 ( 4H, m)

[0825] 质量(m/e)244(M+1) [0825] mass (m / e) 244 (M + 1)

[0826] 制备62:2-环戊基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0826] Preparation 62: 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0827] (1)合成2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [0827] (1) Synthesis of 2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[0828] 将制备47获得的1.0g(3.39mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯溶解于10mL吡啶,然后其中加入380mg(3.39mmol)环戊烷脒盐酸盐,反应液加热至120℃,搅拌1小时20分钟。 [0828] The preparation 47 1.0g (3.39mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained - butyl ester was dissolved in 10mL pyridine, and then was added 380mg (3.39mmol) cyclopentane hydrochloride, the reaction was heated to 120 deg.] C, stirred for 1 hour 20 minutes. 冷却至室温之后,减压下去除吡啶。 After cooling to room temperature, pyridine was removed under reduced pressure. 残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到688mg标题化合物,收率55%。 The residue was purified by column chromatography (10:1 hexanes: ethyl acetate) to give 688mg of the title compound in 55% yield.

[0829] 1H NMR(CDCl3)δ4.67(2H,s),3.70(2H,t,J=5.5Hz),3.34(1H,m),2.96(2H,br s),2.07(2H,m),1.8-2.0(4H,m),1.70(2H,m),1.49(9H,s) [0829] 1H NMR (CDCl3) δ4.67 (2H, s), 3.70 (2H, t, J = 5.5Hz), 3.34 (1H, m), 2.96 (2H, br s), 2.07 (2H, m) , 1.8-2.0 (4H, m), 1.70 (2H, m), 1.49 (9H, s)

[0830] 质量(m/e)372(M+1) [0830] mass (m / e) 372 (M + 1)

[0831] (2)合成2-环戊基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0831] (2) Synthesis of 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0832] 除了利用上述步骤(1)获得的688mg(1.85mmol)2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备58(3)的相同方式,获得480mg标题化合物,收率84%。 [0832] In addition to the above steps (1) obtained 688mg (1.85mmol) 2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as preparation 58 (3), to obtain 480mg of the title compound in 84% yield.

[0833] 1H NMR(CD3OD)δ4.44(2H,s),3.58(2H,t,J=6.5Hz),3.4(1H,m),3.20(2H,t,J=6.5Hz),2.07(2H,m),1.8-2.0(4H,m),1.70(2H,m) [0833] 1H NMR (CD3OD) δ4.44 (2H, s), 3.58 (2H, t, J = 6.5Hz), 3.4 (1H, m), 3.20 (2H, t, J = 6.5Hz), 2.07 ( 2H, m), 1.8-2.0 (4H, m), 1.70 (2H, m)

[0834] 质量(m/e)272(M+1) [0834] mass (m / e) 272 (M + 1)

[0835] 制备63:合成2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0835] Preparation 63: Synthesis of 2-phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0836] (1)合成2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [0836] (1) Synthesis of 2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[0837] 除了利用制备47获得的1.0g(3.39mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和530mg(3.39mmol)苯脒盐酸盐之外,以制备61-(1)的相同方式,获得900mg标题化合物,收率70%。 [0837] Preparation 47 except for using the obtained 1.0g (3.39mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester and 530mg (3.39mmol) of benzamidine hydrochloride in addition, in the same manner as the preparation of 61- (1), to obtain 900mg of the title compound in 70% yield.

[0838] 1H NMR(CDCl3)δ8.46(2H,m),7.49(3H,m),4.78(2H,s),3.75(2H,t,J=5.5Hz),3.03(2H,br s),1.51(9H,s) [0838] 1H NMR (CDCl3) δ8.46 (2H, m), 7.49 (3H, m), 4.78 (2H, s), 3.75 (2H, t, J = 5.5Hz), 3.03 (2H, br s) , 1.51 (9H, s)

[0839] 质量(m/e)380(M+1) [0839] mass (m / e) 380 (M + 1)

[0840] (2)合成2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [0840] (2) Synthesis of 2-phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[0841] 除了利用上述步骤(1)获得的900mg(2.37mmol)2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备58(3)的相同方式,获得730mg标题化合物,收率97%。 [0841] 900mg except for using the above-described step (1) obtained in (2.37mmol) 2- phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - carboxylic acid tert - butyl ester addition, in the same manner as preparation 58 (3), to obtain 730mg of the title compound in 97% yield.

[0842] 1H NMR(CD3OD)δ8.50(2H,m),7.57(3H,m),4.61(2H,s),3.67(2H,t,J=7.5Hz),3.30(2H,m) [0842] 1H NMR (CD3OD) δ8.50 (2H, m), 7.57 (3H, m), 4.61 (2H, s), 3.67 (2H, t, J = 7.5Hz), 3.30 (2H, m)

[0843] 质量(m/e)280(M+1) [0843] mass (m / e) 280 (M + 1)

[0844] 制备64:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [0844] Preparation 64: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[0845] 以制备45的相同方式,将制备51获得的77mg(0.24mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5R-甲基-2-氧代哌啶-1-基)-丁酸与制备63获得的70mg(0.22mmol)2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐反应,得到120mg标题化合物,收率94%。 [0845] In the same manner as in Preparation 45, the preparation obtained in 51 77mg (0.24mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5R--methyl-2-oxo piperidin-1-yl) - butanoic acid obtained in preparation 63 70mg (0.22mmol) 2- phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- -d] pyrimidine hydrochloric acid salt to give the title compound 120mg, 94% yield.

[0846] 1H NMR(CDCl3)δ8.46(2H,m),7.50(3H,m),5.86(1H,m),4.93(1H,s),4.8(1H,ABq,J=16Hz),4.2(1H,m),3.92(1H,m),3.8(1H,m),3.63(1H,m),3.36(1H,m),3.0-3.2(3H,m),2.88(1H,m),2.3-2.6(3H,m),1.8-2.0(2H,m),1.40(9H,m),1.00(3H,d,J=6.5Hz) [0846] 1H NMR (CDCl3) δ8.46 (2H, m), 7.50 (3H, m), 5.86 (1H, m), 4.93 (1H, s), 4.8 (1H, ABq, J = 16Hz), 4.2 (1H, m), 3.92 (1H, m), 3.8 (1H, m), 3.63 (1H, m), 3.36 (1H, m), 3.0-3.2 (3H, m), 2.88 (1H, m), 2.3-2.6 (3H, m), 1.8-2.0 (2H, m), 1.40 (9H, m), 1.00 (3H, d, J = 6.5Hz)

[0847] 质量(m/e)576(M+1) [0847] mass (m / e) 576 (M + 1)

[0848] 实施例22:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [0848] Example 22: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[0849] [0849]

[0850] 将制备64获得的120mg(0.21mmol){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯溶解于1,4-二噁烷/盐酸。 [0850] A 120mg (0.21mmol) {(1S) obtained in Preparation 64 -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo 3- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester was dissolved in 1,4-dioxane / hydrochloric acid. 搅拌30分钟之后,减压下浓缩,残留物通过prep-TLC纯化(10∶1CH2Cl2∶MeOH),得到83mg标题化合物,收率84%。 After stirring for 30 minutes, concentrated under reduced pressure, the residue was purified by prep-TLC (10:1CH2Cl2:MeOH) to afford 83mg of the title compound in 84% yield.

[0851] 1H NMR(CD3OD)δ8.46(2H,m),7.50(3H,m),5.0-4.8(2H,m),3.94(1H,t,J=6.5Hz),3.86(1H,m),3.75(1H,m),3.64(1H,m),3.53(1H,m),3.3-3.4(1H,m),3.0-3.2(3H,m),2.86(1H,m),2.70(1H,m),2.3-2.5(2H,m),2.0(1H,m),1.84(1H,m),1.52(1H,m),1.02(3H,m) [0851] 1H NMR (CD3OD) δ8.46 (2H, m), 7.50 (3H, m), 5.0-4.8 (2H, m), 3.94 (1H, t, J = 6.5Hz), 3.86 (1H, m ), 3.75 (1H, m), 3.64 (1H, m), 3.53 (1H, m), 3.3-3.4 (1H, m), 3.0-3.2 (3H, m), 2.86 (1H, m), 2.70 ( 1H, m), 2.3-2.5 (2H, m), 2.0 (1H, m), 1.84 (1H, m), 1.52 (1H, m), 1.02 (3H, m)

[0852] 质量(m/e)476(M+1) [0852] mass (m / e) 476 (M + 1)

[0853] 制备65:合成[(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基]氨基甲酸叔-丁酯 [0853] Preparation 65: Synthesis of [(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [2- phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl] carbamic acid tert - butyl ester

[0854] 除了利用制备55获得的77mg(0.24mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]-丁酸和制备63获得的70mg(0.22mmol)2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得182mg标题化合物,收率99%。 [0854] Preparation 55 except using the obtained 77mg (0.24mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-morpholine 4-yl] - preparation 63 and butyric acid obtained 70mg (0.22mmol) 2- phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d ] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 182mg of the title compound in 99% yield.

[0855] 1H NMR(CDCl3)δ8.46(2H,m),7.51(3H,m),5.80(1H,m),4.93(1H,s),4.8(1H,ABq,J=16Hz),4.2-4.3(2H,m),3.8-4.0(3H,m),3.6-3.7(1H,m),3.5-3.6(1H,m),3.3-3.4(2H,m),3.0-3.2(2H,m),2.8-2.9(1H,m),2.5-2.6(1H,m),1.41(9H,m),1.26(3H,d,J=6.5Hz) [0855] 1H NMR (CDCl3) δ8.46 (2H, m), 7.51 (3H, m), 5.80 (1H, m), 4.93 (1H, s), 4.8 (1H, ABq, J = 16Hz), 4.2 -4.3 (2H, m), 3.8-4.0 (3H, m), 3.6-3.7 (1H, m), 3.5-3.6 (1H, m), 3.3-3.4 (2H, m), 3.0-3.2 (2H, m), 2.8-2.9 (1H, m), 2.5-2.6 (1H, m), 1.41 (9H, m), 1.26 (3H, d, J = 6.5Hz)

[0856] 质量(m/e)578(M+1) [0856] mass (m / e) 578 (M + 1)

[0857] 实施例23:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮 [0857] Example 23: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -6-methylmorpholine-3-one

[0858] [0858]

[0859] 除了利用制备65获得的127mg(0.22mmol)[(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}3-氧代-3-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基]氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得91mg标题化合物,收率87%。 [0859] Besides using 127mg (0.22mmol) [(1S) obtained in Preparation 65 -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} 3-oxo 3- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl] carbamic acid tert - butyl ester addition, in the same manner as Example 23 to obtain 91mg of the title compound in 87% yield.

[0860] 1H NMR(CD3OD)δ8.46(2H,m),7.50(3H,m),5.0-4.8(2H,m),4.0-4.2(2H,m),3.8-4.0(3H,m),3.7-3.8(1H,m),3.5-3.6(2H,m),3.53(1H,m),3.3-3.4(2H,m),3.0-3.2(2H,m),2.8-2.9(1H,m),2.6-2.7(1H,m),1.23(3H,m) [0860] 1H NMR (CD3OD) δ8.46 (2H, m), 7.50 (3H, m), 5.0-4.8 (2H, m), 4.0-4.2 (2H, m), 3.8-4.0 (3H, m) , 3.7-3.8 (1H, m), 3.5-3.6 (2H, m), 3.53 (1H, m), 3.3-3.4 (2H, m), 3.0-3.2 (2H, m), 2.8-2.9 (1H, m), 2.6-2.7 (1H, m), 1.23 (3H, m)

[0861] 质量(m/e)478(M+1) [0861] mass (m / e) 478 (M + 1)

[0862] 制备66:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]3-氢代-3-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [0862] Preparation 66: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] Hydrogen-3- 3- [2-phenyl - 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[0863] 除了利用制备57获得的82mg(0.24mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸和制备63获得的70mg(0.22mmol)2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得108mg标题化合物,收率82%。 [0863] Besides using 82mg (0.24mmol) (3S) -3 obtained in Preparation 57 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) - butanoic acid 63 was prepared and obtained 70mg (0.22mmol) 2- phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride in the same manner as in preparation 45, to obtain 108mg of the title compound in 82% yield.

[0864] 1H NMR(CDCl3)δ8.46(2H,m),7.50(3H,m),5.78(1H,m),4.93(1H,s),4.78(1H,ABq,J=16Hz),4.22(1H,m),3.92(1H,m),3.7-3.8(3H,m),3.5-3.7(2H,m),3.0-3.2(2H,m),2.84(1H,m),2.56(3H,m),2.27(2H,m),1.41(9H,m) [0864] 1H NMR (CDCl3) δ8.46 (2H, m), 7.50 (3H, m), 5.78 (1H, m), 4.93 (1H, s), 4.78 (1H, ABq, J = 16Hz), 4.22 (1H, m), 3.92 (1H, m), 3.7-3.8 (3H, m), 3.5-3.7 (2H, m), 3.0-3.2 (2H, m), 2.84 (1H, m), 2.56 (3H , m), 2.27 (2H, m), 1.41 (9H, m)

[0865] 质量(m/e)598(M+1) [0865] mass (m / e) 598 (M + 1)

[0866] 实施例24:合成1-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [0866] Example 24: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[0867] [0867]

[0868] 除了利用制备65获得的108mg(0.18mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]3-氧代-3-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得78mg标题化合物,收率87%。 [0868] Besides using 108mg (0.18mmol) {(1S) -1 obtained in Preparation 65 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- - [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester of in addition, in the same manner as Example 23 to obtain 78mg of the title compound in 87% yield.

[0869] 1H NMR(CD3OD)δ8.46(2H,m),7.50(3H,m),5.0-4.8(2H,m),3.6-4.0(6H,m),3.48(1H,m),3.0-3.2(2H,m),2.83(1H,m),2.71(1H,m),2.57(2H,m),2.34(2H,m) [0869] 1H NMR (CD3OD) δ8.46 (2H, m), 7.50 (3H, m), 5.0-4.8 (2H, m), 3.6-4.0 (6H, m), 3.48 (1H, m), 3.0 -3.2 (2H, m), 2.83 (1H, m), 2.71 (1H, m), 2.57 (2H, m), 2.34 (2H, m)

[0870] 质量(m/e)498(M+1) [0870] mass (m / e) 498 (M + 1)

[0871] 制备67:{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [0871] Preparation 67: {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2-cyclopropyl-4- (C fluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[0872] 除了利用制备57获得的8.4mg(0.024mmol)(3S)-3-[(叔-丁氧羧基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备61获得的7mg(0.025mmol)2-环丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得12mg(0.021mmol)标题化合物,收率87%。 [0872] Besides using 8.4mg (0.024mmol) (3S) -3 obtained in Preparation 57 - [- (tert-butoxy carboxyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butanoic acid obtained in preparation 61 and 7mg (0.025mmol) 2- cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride in the same manner as in preparation 45 to give 12mg (0.021mmol) of the title compound in 87% yield.

[0873] 质量(EI)562(M++1) [0873] mass (EI) 562 (M ++ 1)

[0874] 实施例25:合成1-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [0874] Example 25: Synthesis of 1 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[0875] [0875]

[0876] 除了利用制备67获得的12mg(0.021mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得6mg(0.012mmol)标题化合物,收率57%。 [0876] Besides using 12mg (0.021mmol) {(1S) -1 obtained in Preparation 67 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as Example 23 to obtain 6mg (0.012mmol) of the title compound in 57% yield.

[0877] NMR:1H-NMR(CD3OD)δ4.84~4.73(2H,m),3.89~3.76(4H,m),3.55~3.47(3H,m),3.10~2.96(2H,m),2.69~2.55(4H,m),2.39~2.17(3H,m),1.17~1.12(4H,m) [0877] NMR: 1H-NMR (CD3OD) δ4.84 ~ 4.73 (2H, m), 3.89 ~ 3.76 (4H, m), 3.55 ~ 3.47 (3H, m), 3.10 ~ 2.96 (2H, m), 2.69 ~ 2.55 (4H, m), 2.39 ~ 2.17 (3H, m), 1.17 ~ 1.12 (4H, m)

[0878] 质量(EI)462(M++1) [0878] mass (EI) 462 (M ++ 1)

[0879] 制备68:合成(1S)-1-{[5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [0879] Preparation 68: Synthesis of (1S) -1 - {[5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3- [2-cyclopropyl-4- ( trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[0880] 除了利用制备51获得的8.0mg(0.025mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备61获得的7mg(0.025mmol)2-环丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得11mg(0.020mmol)标题化合物,收率80%。 [0880] Besides using 8.0mg (0.025mmol) (3S) -3 obtained in Preparation 51 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxo-piperazine l-yl] butanoic acid obtained in preparation 61 and 7mg (0.025mmol) 2- cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 11mg (0.020mmol) of the title compound in 80% yield.

[0881] 质量(EI)540(M++1) [0881] mass (EI) 540 (M ++ 1)

[0882] 实施例26:合成1-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [0882] Example 26: Synthesis of 1 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[0883] [0883]

[0884] 除了利用制备68获得的11mg(0.020mmol)(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得7mg(0.014mmol)标题化合物,收率70%。 [0884] Besides using 11mg (0.020mmol) (1S) -1 obtained in Preparation 68 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3- [2 - cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 23, to obtain 7mg (0.014mmol) of the title compound in 70% yield.

[0885] NMR:1H-NMR(CD3OD)δ4.80~4.73(2H,m),3.89~3.81(2H,m),3.70~3.60(1H,m),3.52~3.50(2H,m),3.40~3.37(1H,m),3.10~2.90(3H,m),2.77~2.72(1H,m),2.65~2.59(1H,m),2.42~2.17(3H,m),2.10~1.95(1H,m),1.90~1.80(1H,m),1.58~1.49(1H,m),1.13(3H,d,J=6.4Hz),1.04(4H,d,J=6.4Hz) [0885] NMR: 1H-NMR (CD3OD) δ4.80 ~ 4.73 (2H, m), 3.89 ~ 3.81 (2H, m), 3.70 ~ 3.60 (1H, m), 3.52 ~ 3.50 (2H, m), 3.40 ~ 3.37 (1H, m), 3.10 ~ 2.90 (3H, m), 2.77 ~ 2.72 (1H, m), 2.65 ~ 2.59 (1H, m), 2.42 ~ 2.17 (3H, m), 2.10 ~ 1.95 (1H, m), 1.90 ~ 1.80 (1H, m), 1.58 ~ 1.49 (1H, m), 1.13 (3H, d, J = 6.4Hz), 1.04 (4H, d, J = 6.4Hz)

[0886] 质量(EI)440(M++1) [0886] mass (EI) 440 (M ++ 1)

[0887] 制备69:合成(1S)-1-{[(2R)-2-甲基-5-氧代吗啉-4-基]甲基}-3-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [0887] Preparation 69: Synthesis of (1S) -1 - {[(2R) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[0888] 除了利用制备55获得的8.0mg(0.025mmol)(3S)-3-[(叔-丁氧羧基)氨基]-4-[(2S)-2-甲基-5-氧代哌啶-吗啉-4-基]丁酸和制备61获得的7mg(0.025mmol)2-环丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得12mg(0.022mmol)标题化合物,收率88%。 [0888] Besides using 8.0mg (0.025mmol) (3S) -3 obtained in Preparation 55 - [- (tert-butoxy carboxyl) amino] -4 - [(2S) -2- methyl-5-oxo-piperidine - morpholin-4-yl] butanoic acid obtained in preparation 61 and 7mg (0.025mmol) 2- cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, other than 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 12mg (0.022mmol) of the title compound in 88% yield.

[0889] 质量(EI)528(M++1) [0889] mass (EI) 528 (M ++ 1)

[0890] 实施例27:合成(6S)-4-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 [0890] Example 27: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[0891] [0891]

[0892] 除了利用制备69获得的12mg(0.022mmol)(1S)-1-{[(2R)-2-甲基-5-氧代吗啉-4-基]甲基}-3-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得7mg(0.014mmol)标题化合物,收率63%。 [0892] Besides using 12mg (0.022mmol) (1S) -1 obtained in Preparation 69 - {[(2R) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- [2 - cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 23, to obtain 7mg (0.014mmol) of the title compound in 63% yield.

[0893] NMR:1H-NMR(CD3OD)δ4.80~4.73(2H,m),4.20~4.13(2H,m),3.97~3.82(3H,m),3.60~3.52(2H,m),3.46~3.32(3H,m),3.10~3.05(1H,m),3.00~2.94(1H,m),2.73~2.68(1H,m),2.62~2.56(1H,m),2.30~2.17(1H,m),1.25(3H,d,J=6.0Hz),1.15(4H,d,J=9.2Hz) [0893] NMR: 1H-NMR (CD3OD) δ4.80 ~ 4.73 (2H, m), 4.20 ~ 4.13 (2H, m), 3.97 ~ 3.82 (3H, m), 3.60 ~ 3.52 (2H, m), 3.46 ~ 3.32 (3H, m), 3.10 ~ 3.05 (1H, m), 3.00 ~ 2.94 (1H, m), 2.73 ~ 2.68 (1H, m), 2.62 ~ 2.56 (1H, m), 2.30 ~ 2.17 (1H, m), 1.25 (3H, d, J = 6.0Hz), 1.15 (4H, d, J = 9.2Hz)

[0894] 质量(EI)442(M++1) [0894] mass (EI) 442 (M ++ 1)

[0895] 制备70:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丙基}氨基甲酸叔-丁酯 [0895] Preparation 70: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [5- (C fluoro-methyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] propyl} carbamic acid tert - butyl ester

[0896] 除了利用制备57获得的31mg(0.092mmol)(3S)-3-[(叔-丁氧羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和参照WO 03/093231获得的20mg(0.099mmol)5-(三氟甲基)-1,2,3,4-四氢异喹啉之外,以制备45的相同方式,获得12mg(0.023mmol)标题化合物,收率25%。 [0896] Preparation 57 except using the obtained 31mg (0.092mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 outside-yl) butyric acid and obtained with reference to WO 03/093231 20mg (0.099mmol) 5- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline, prepared in the same manner as 45, to obtain 12mg (0.023mmol) of the title compound in a yield of 25%.

[0897] 质量(EI)520(M++1) [0897] mass (EI) 520 (M ++ 1)

[0898] 实施例28:合成1-{(2S)-2-氨基-4-氧代-4-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丁基}-5,5-二氟哌啶-2-酮 [0898] Example 28: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] butyl} -5,5-difluoropiperidin-2-one

[0899] [0899]

[0900] 除了利用制备70获得的12mg(0.023mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得6mg(0.012mmol)标题化合物,收率57%。 [0900] Preparation 70 except for using the obtained 12mg (0.023mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo - 3- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] propyl} carbamic acid tert - butyl ester addition, in the same manner as Example 23 to give 6mg (0.012mmol) of the title compound in 57% yield.

[0901] NMR:1H-NMR(CD3OD)δ7.61~7.38(3H,m),4.79~4.78(2H,m),3.84~3.75(4H,m),3.67~3.62(2H,m),3.48~3.46(1H,m),3.15~3.12(1H,m),3.04~3.02(1H,m),2.81~2.70(1H,m),2.66~2.56(3H,m),2.41~2.32(2H,m) [0901] NMR: 1H-NMR (CD3OD) δ7.61 ~ 7.38 (3H, m), 4.79 ~ 4.78 (2H, m), 3.84 ~ 3.75 (4H, m), 3.67 ~ 3.62 (2H, m), 3.48 ~ 3.46 (1H, m), 3.15 ~ 3.12 (1H, m), 3.04 ~ 3.02 (1H, m), 2.81 ~ 2.70 (1H, m), 2.66 ~ 2.56 (3H, m), 2.41 ~ 2.32 (2H, m)

[0902] 质量(EI)420(M++1) [0902] mass (EI) 420 (M ++ 1)

[0903] 制备71:合成{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丙基}氨基甲酸叔-丁酯 [0903] Preparation 71: Synthesis of {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] propyl} carbamic acid tert - butyl ester

[0904] 除了利用制备55获得的31mg(0.097mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代哌啶-吗啉-4-基]丁酸和参照WO03/093231获得的5-(三氟甲基)-1,2,3,4-四氢异喹啉20mg(0.099mmol)之外,以制备45的相同方式,获得10mg(0.020mmol)标题化合物,收率20%。 [0904] Preparation 55 except using the obtained 31mg (0.097mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-piperidine - addition morpholin-4-yl] butanoic acid and reference WO03 / 093231 5- (trifluoromethyl) -1,2,3,4-tetrahydro-obtained isoquinoline 20mg (0.099mmol), to prepare a 45 in the same manner to obtain 10mg (0.020mmol) of the title compound in 20% yield.

[0905] 质量(EI)500(M++1) [0905] mass (EI) 500 (M ++ 1)

[0906] 实施例29:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丁基}-6-甲基吗啉-3-酮 [0906] Example 29: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline - 2 (1H) - yl] butyl} -6-methylmorpholine-3-one

[0907] [0907]

[0908] 除了利用制备76获得的10mg(0.020mmol){(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例23的相同方式,获得6mg(0.013mmol)标题化合物,收率65%。 [0908] Besides using 10mg (0.020mmol) {(1S) obtained in Preparation 76 -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo -3- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] propyl} carbamic acid tert - butyl ester addition, in the same manner as Example 23 to give 6mg (0.013mmol) of the title compound in 65% yield.

[0909] NMR:1H-NMR(CD3OD)δ7.61~7.40(3H,m),4.87~4.79(2H,m),4.20~4.07(2H,m),3.94~3.90(1H,m),3.82~3.76(2H,m),3.66~3.49(3H,m),3.40~3.35(2H,m),3.14~3.00(2H,m),2.73~2.60(2H,m),1.24(3H,d,J=6Hz) [0909] NMR: 1H-NMR (CD3OD) δ7.61 ~ 7.40 (3H, m), 4.87 ~ 4.79 (2H, m), 4.20 ~ 4.07 (2H, m), 3.94 ~ 3.90 (1H, m), 3.82 ~ 3.76 (2H, m), 3.66 ~ 3.49 (3H, m), 3.40 ~ 3.35 (2H, m), 3.14 ~ 3.00 (2H, m), 2.73 ~ 2.60 (2H, m), 1.24 (3H, d, J = 6Hz)

[0910] 质量(EI)400(M++1) [0910] mass (EI) 400 (M ++ 1)

[0911] 制备72:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [0911] Preparation 72: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (4-fluorophenyl) 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[0912] 除了利用制备57获得的16mg(0.067mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备58获得的20mg(0.067mmol)2-(4-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得22mg标题化合物,收率53%。 [0912] Preparation 57 except for using the obtained 16mg (0.067mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butanoic acid obtained and prepared 20mg (0.067mmol) 2- (4- 58 fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition -d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 22mg of the title compound in 53% yield.

[0913] 1H NMR(CDCl3)δ8.48-8.46(2H,m),7.18-7.16(2H,m),5.79-5.77(1H,m),4.94-4.88(1H,m),4.82-4.72(1H,m),4.21(1H,brs),3.94-3.88(1H,m),3.80-3.70(3H,m),3.62-3.58(1H,m),3.12-3.03(2H,m),2.87-2.82(1H,m),2.60-2.52(4H,m),2.28-2.23(2H,m),1.41-1.40(9H,m) [0913] 1H NMR (CDCl3) δ8.48-8.46 (2H, m), 7.18-7.16 (2H, m), 5.79-5.77 (1H, m), 4.94-4.88 (1H, m), 4.82-4.72 ( 1H, m), 4.21 (1H, brs), 3.94-3.88 (1H, m), 3.80-3.70 (3H, m), 3.62-3.58 (1H, m), 3.12-3.03 (2H, m), 2.87- 2.82 (1H, m), 2.60-2.52 (4H, m), 2.28-2.23 (2H, m), 1.41-1.40 (9H, m)

[0914] 质量(m/e)516(M+1-BOC) [0914] mass (m / e) 516 (M + 1-BOC)

[0915] 实施例30:合成1-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 30 [0915] Example: Synthesis of 1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[0916] [0916]

[0917] 除了利用制备72获得22mg(0.036mmol)的{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得15.3mg标题化合物,收率78%。 [0917] In addition to using Preparation 72 to obtain 22mg (0.036mmol) of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} amino acid tert - butyl ester addition, in the same manner as Example 22 to give the title compound 15.3mg, 78% yield.

[0918] 1H NMR(CD3OD)δ8.49-8.48(2H,m),7.23-7.20(2H,m),4.90-4.85(2H,m),3.95-3.70(5H,m),3.50-3.46(1H,m),3.30-3.28(1H,m),3.13(1H,brs),3.03(1H,brs),2.90-2.86(1H,m),2.76-2.72(1H,m),2.58-2.54(2H,m),2.37-2.32(2H,m) [0918] 1H NMR (CD3OD) δ8.49-8.48 (2H, m), 7.23-7.20 (2H, m), 4.90-4.85 (2H, m), 3.95-3.70 (5H, m), 3.50-3.46 ( 1H, m), 3.30-3.28 (1H, m), 3.13 (1H, brs), 3.03 (1H, brs), 2.90-2.86 (1H, m), 2.76-2.72 (1H, m), 2.58-2.54 ( 2H, m), 2.37-2.32 (2H, m)

[0919] 质量(m/e)516(M+1) [0919] mass (m / e) 516 (M + 1)

[0920] 制备73:合成[(1S)-3-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[2S)-2-甲基-5-氧代吗啉-4-基]甲基}3-氧代丙基]氨基甲酸叔-丁酯 [0920] Preparation 73: Synthesis of [(1S) -3- [2- (4- fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - {[2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} 3-oxopropyl] carbamic acid tert - butyl ester

[0921] 除了利用制备55获得的21.2mg(0.067mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸和制备58获得的20mg(0.067mmol)2-(4-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得26mg标题化合物,收率40%。 [0921] Preparation 55 except using the obtained 21.2mg (0.067mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 morpholin-4-yl] butanoic acid obtained and 20mg (0.067mmol) 2- (4- fluorophenyl) preparation 58 4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido addition [3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 26mg of the title compound in 40% yield.

[0922] 1H NMR(CDCl3)δ8.49-8.46(2H,m),7.17-7.15(2H,m),5.81-5.76(1H,m),4.96-4.88(1H,m),4.83-4.72(1H,m),4.23-4.09(3H,m),3.93-3.85(2H,m),3.79(1H,brs),3.68-3.61(1H,m),3.54-3.48(1H,m),3.39-3.30(2H,m),3.10-3.03(3H,m),2.60-2.53(1H,m),1.42-1.41(9H,m),1.25(3H,d,J=6.1Hz), [0922] 1H NMR (CDCl3) δ8.49-8.46 (2H, m), 7.17-7.15 (2H, m), 5.81-5.76 (1H, m), 4.96-4.88 (1H, m), 4.83-4.72 ( 1H, m), 4.23-4.09 (3H, m), 3.93-3.85 (2H, m), 3.79 (1H, brs), 3.68-3.61 (1H, m), 3.54-3.48 (1H, m), 3.39- 3.30 (2H, m), 3.10-3.03 (3H, m), 2.60-2.53 (1H, m), 1.42-1.41 (9H, m), 1.25 (3H, d, J = 6.1Hz),

[0923] 质量(m/e)496(M+1-BOC) [0923] mass (m / e) 496 (M + 1-BOC)

[0924] 实施例31:合成(6S)-4-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-2-酮 31 [0924] Example: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl morpholin-2-one

[0925] [0925]

[0926] 除了利用制备73获得的26mg(0.044mmol)[(1S)-3-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}3-氧代丙基]氨基甲酸叔-丁酯之外,以制备22的相同方式,获得17.8mg标题化合物,收率77%。 [0926] Preparation 73 except using the obtained 26mg (0.044mmol) [(1S) -3- [2- (4- fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} 3-oxopropyl] carbamic acid tert - butyl ester addition, in the same manner as in preparation 22 to give 17.8mg of the title compound in 77% yield.

[0927] 1H NMR(CD3OD)δ8.49-8.48(2H,m),7.24-7.21(2H,m),4.97-4.85(2H,m),4.20-4.10(2H,m),3.96-3.93(2H,m),3.87-3.84(1H,m),3.79(1H,brs),3.67-3.55(2H,m),3.33-3.30(2H,m),2.13(1H,brs),3.03(1H,brs),2.91-2.87(1H,m),2.76-2.71(1H,m),1.24-1.22(3H,m) [0927] 1H NMR (CD3OD) δ8.49-8.48 (2H, m), 7.24-7.21 (2H, m), 4.97-4.85 (2H, m), 4.20-4.10 (2H, m), 3.96-3.93 ( 2H, m), 3.87-3.84 (1H, m), 3.79 (1H, brs), 3.67-3.55 (2H, m), 3.33-3.30 (2H, m), 2.13 (1H, brs), 3.03 (1H, brs), 2.91-2.87 (1H, m), 2.76-2.71 (1H, m), 1.24-1.22 (3H, m)

[0928] 质量(m/e)496(M+1) [0928] mass (m / e) 496 (M + 1)

[0929] 制备74:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-{2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基}-3-氧代丙基}氨基甲酸叔-丁酯 [0929] Preparation 74: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- {2- (3-fluorophenyl) 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl} -3-oxopropyl} carbamic acid tert - butyl ester

[0930] 除了利用制备57获得的22.6mg(0.067mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备60获得的20mg(0.067mmol)2-(3-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得27mg标题化合物,收率72%。 [0930] Preparation 57 except for using the obtained 22.6mg (0.067mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin - 20mg 1- yl) butyric acid and obtained in preparation 60 (0.067mmol) 2- (3- fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, other than 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 27mg, 72% yield.

[0931] 1H NMR(CDCl3)δ8.29-8.25(1H,m),8.18-8.15(1H,m),7.53-7.44(1H,m),7.24-7.19(1H,m)5.81-5.79(1H,m),4.99-4.88(1H,m),4.85-4.75(1H,m),4.23(1H,brs),3.94-3.91(1H,m),3.81-3.67(4H,m),3.64-3.58(2H,m),3.12-3.06(2H,m),2.88-2.84(1H,m),2.63-2.54(3H,m),2.27-2.24(1H,m),1.43-1.41(9H,m) [0931] 1H NMR (CDCl3) δ8.29-8.25 (1H, m), 8.18-8.15 (1H, m), 7.53-7.44 (1H, m), 7.24-7.19 (1H, m) 5.81-5.79 (1H , m), 4.99-4.88 (1H, m), 4.85-4.75 (1H, m), 4.23 (1H, brs), 3.94-3.91 (1H, m), 3.81-3.67 (4H, m), 3.64-3.58 (2H, m), 3.12-3.06 (2H, m), 2.88-2.84 (1H, m), 2.63-2.54 (3H, m), 2.27-2.24 (1H, m), 1.43-1.41 (9H, m)

[0932] 质量(m/e)516(M+1-BOC) [0932] mass (m / e) 516 (M + 1-BOC)

[0933] 实施例32:合成1-{(2S)-2-氨基-4-[2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 32 [0933] Example: Synthesis of 1 - {(2S) -2- amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[0934] [0934]

[0935] 除了利用制备74获得的27mg(0.044mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-{2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-y1}-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得18.5mg标题化合物,收率76%。 [0935] Preparation 74 except using the obtained 27mg (0.044mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- {2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) -y1} -3- oxopropyl} amino acid tert - butyl ester addition, in the same manner as Example 22 to give the title compound 18.5mg, yield 76%.

[0936] 1H NMR(CD3OD)δ8.31-8.28(1H,m),8.16-8.12(1H,m),7.57-7.51(1H,m),7.31-7.26(1H,m)5.00-4.88(2H,m),3.99-3.88(2H,m),3.85-3.77(2H,m),3.58-3.53(1H,m),3.51-3.46(2H,m),3.16(1H,brs),3.06(1H,brs),2.75-2.70(1H,m),2.63-2.52(3H,m),2.40-2.32(2H,m) [0936] 1H NMR (CD3OD) δ8.31-8.28 (1H, m), 8.16-8.12 (1H, m), 7.57-7.51 (1H, m), 7.31-7.26 (1H, m) 5.00-4.88 (2H , m), 3.99-3.88 (2H, m), 3.85-3.77 (2H, m), 3.58-3.53 (1H, m), 3.51-3.46 (2H, m), 3.16 (1H, brs), 3.06 (1H , brs), 2.75-2.70 (1H, m), 2.63-2.52 (3H, m), 2.40-2.32 (2H, m)

[0937] 质量(m/e)516(M+1) [0937] mass (m / e) 516 (M + 1)

[0938] 制备75:合成[(1S)-3-[2-(3-氟苯基)-4-(三氟)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [0938] Preparation 75: Synthesis of [(1S) -3- [2- (3- fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[0939] 除了利用制备55获得的21.2mg(0.067mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸和制备60获得的20mg(0.067mmol)2-(3-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45相同的方式,获得27mg标题化合物,收率68%。 [0939] Preparation 55 except using the obtained 21.2mg (0.067mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 20mg morpholin-4-yl] butanoic acid obtained in preparation 60 and (0.067mmol) 2- (3- fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido addition [3,4-d] pyrimidine hydrochloride, prepared in the same manner as 45, to obtain 27mg of the title compound in 68% yield.

[0940] 1H NMR(CDCl3) [0940] 1H NMR (CDCl3)

8.33-8.29(1H,m),8.22-8.19(1H,m),7.54-7.48(1H,m),7.28-7.23(1H,m)5.86-5.81(1H,m),5.03-4.92(1H,m),4.90-4.79(1H,m),4.29-4.23(2H,m),4.19-4.15(1H,m),4.00-3.90(2H,m),3.85(1H,brs),3.75-3.68(1H,m),3.59-3.52(1H,m),3.45-3.35(2H,m),3.15-3.10(2H,m),2.96-2.90(1H,m),2.64-2.60(1H,m),1.47-1.46(9H,m),1.32-1.28(3H,m) 8.33-8.29 (1H, m), 8.22-8.19 (1H, m), 7.54-7.48 (1H, m), 7.28-7.23 (1H, m) 5.86-5.81 (1H, m), 5.03-4.92 (1H, m), 4.90-4.79 (1H, m), 4.29-4.23 (2H, m), 4.19-4.15 (1H, m), 4.00-3.90 (2H, m), 3.85 (1H, brs), 3.75-3.68 ( 1H, m), 3.59-3.52 (1H, m), 3.45-3.35 (2H, m), 3.15-3.10 (2H, m), 2.96-2.90 (1H, m), 2.64-2.60 (1H, m), 1.47-1.46 (9H, m), 1.32-1.28 (3H, m)

[0941] 质量(m/e)496(M+1-BOC) [0941] mass (m / e) 496 (M + 1-BOC)

[0942] 实施例33:合成(6S)-4-{(2S)-2-氨基-4-[2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 33 [0942] Example: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[0943] [0943]

[0944] 除了利用制备75获得的27mg(0.045mmol)[(1S)-3-[2-(3-氟苯基)-4-(三氟)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得16.5mg标题化合物,收率68%。 [0944] (0.045mmol) [(1S) -3- [2- (3- fluorophenyl) Preparation 75 except using the obtained 27mg of 4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] amino acid tert - butyl ester addition, in the same manner as Example 22 to give the title compound 16.5mg, 68% yield.

[0945] 1H NMR(CD3OD)δ8.30-8.28(1H,m),8.16-8.12(1H,m),7.57-7.51(1H,m),7.31-7.26(1H,m)5.01-4.88(2H,m),4.21-4.09(2H,m),4.00-3.84(3H,m),3.64-3.54(2H,m),3.46-3.35(3H,m),3.16(1H,brs),3.06(1H,brs),2.78-2.72(1H,m),2.64-2.57(1H,m),1.27-1.24(3H,m) [0945] 1H NMR (CD3OD) δ8.30-8.28 (1H, m), 8.16-8.12 (1H, m), 7.57-7.51 (1H, m), 7.31-7.26 (1H, m) 5.01-4.88 (2H , m), 4.21-4.09 (2H, m), 4.00-3.84 (3H, m), 3.64-3.54 (2H, m), 3.46-3.35 (3H, m), 3.16 (1H, brs), 3.06 (1H , brs), 2.78-2.72 (1H, m), 2.64-2.57 (1H, m), 1.27-1.24 (3H, m)

[0946] 质量(m/e)496(M+1) [0946] mass (m / e) 496 (M + 1)

[0947] 制备76:合成[(1S)-3-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [0947] Preparation 76: Synthesis of [(1S) -3- [2- (4- fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[0948] 除了利用制备51获得的28mg(0.094mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备58获得的30mg(0.094mmol)2-(4-氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得29mg标题化合物,收率52%。 [0948] Preparation 51 except for using the obtained 28mg (0.094mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 30mg (0.094mmol) obtained in preparation 58 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3 addition, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 29mg of the title compound in 52% yield.

[0949] 1H NMR(CDCl3)δ8.50-8.46(2H,m),7.26-7.00(2H,m)5.88-5.87(1H,m),4.92(1H,s),4.86-4.74(1H,m),4.21(1H,brs),3.92(1H,brs),3.82-3.79(1H,m),3.64-3.52(2H,m),3.38-3.35(1H,m),3.10-3.04(3H,m),2.87-2.85(1H,m),2.55-2.45(1H,m),2.41-2.21(2H,m),1.95-1.88(1H,m),1.82-1.80(1H,m),1.43-1.41(10H,m),1.01-0.99(3H,m) [0949] 1H NMR (CDCl3) δ8.50-8.46 (2H, m), 7.26-7.00 (2H, m) 5.88-5.87 (1H, m), 4.92 (1H, s), 4.86-4.74 (1H, m ), 4.21 (1H, brs), 3.92 (1H, brs), 3.82-3.79 (1H, m), 3.64-3.52 (2H, m), 3.38-3.35 (1H, m), 3.10-3.04 (3H, m ), 2.87-2.85 (1H, m), 2.55-2.45 (1H, m), 2.41-2.21 (2H, m), 1.95-1.88 (1H, m), 1.82-1.80 (1H, m), 1.43-1.41 (10H, m), 1.01-0.99 (3H, m)

[0950] 质量(m/e)494(M+1-BOC) [0950] mass (m / e) 494 (M + 1-BOC)

[0951] 实施例34:合成(5R)-1-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 34 [0951] Example: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[0952] [0952]

[0953] 除了利用制备76获得的29mg(0.049mmol)[(1S)-3-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得20mg标题化合物,收率77%。 [0953] Preparation 76 except using the obtained 29mg (0.049mmol) [(1S) -3- [2- (4- fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl ] carbamic acid tert - butyl ester addition, in the same manner as Example 22 to obtain 20mg of the title compound in 77% yield.

[0954] 1H NMR(CD3OD)δ8.51-8.48(2H,m),7.25-7.20(2H,m)4.93-4.86(2H,m),3.95-3.92(1H,m),3.87-3.84(1H,m),3.77-3.76(1H,m),3.68-3.61(1H,m),3.54-3.50(1H,m),3.35-3.32(1H,m),3.30-3.29(1H,m),3.13-3.02(2H,m),2.90-2.83(1H,m),2.75-2.70(1H,m),2.44-2.32(2H,m),1.99(1H,brs),1.82(1H,brs),1.52-1.46(1H,m),1.03-1.01(3H,m) [0954] 1H NMR (CD3OD) δ8.51-8.48 (2H, m), 7.25-7.20 (2H, m) 4.93-4.86 (2H, m), 3.95-3.92 (1H, m), 3.87-3.84 (1H , m), 3.77-3.76 (1H, m), 3.68-3.61 (1H, m), 3.54-3.50 (1H, m), 3.35-3.32 (1H, m), 3.30-3.29 (1H, m), 3.13 -3.02 (2H, m), 2.90-2.83 (1H, m), 2.75-2.70 (1H, m), 2.44-2.32 (2H, m), 1.99 (1H, brs), 1.82 (1H, brs), 1.52 -1.46 (1H, m), 1.03-1.01 (3H, m)

[0955] 质量(m/e)494(M+1) [0955] mass (m / e) 494 (M + 1)

[0956] 制备77:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [0956] Preparation 77: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (3,4-difluoro phenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[0957] 除了利用制备57获得的7.0mg(0.020mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备59获得的7.0mg(0.020mmol)2-(3,4-二氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得6.0mg标题化合物,收率47%。 [0957] Besides using 7.0mg (0.020mmol) (3S) -3 obtained in Preparation 57 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin - obtained 7.0mg (0.020mmol) 2- (3,4- difluorophenyl-1-yl) butyric acid and preparation 59) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyridine and [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 6.0mg of the title compound in 47% yield.

[0958] 1H NMR(CDCl3)δ8.33-8.28(2H,m),7.31-7.25(1H,m)5.79-5.78(1H,m),4.98-4.87(1H,m),4.84-4.73(1H,m),4.22-4.21(1H,m),3.93-3.91(1H,m),3.79-3.64(3H,m),3.62-3.56(2H,m),3.12-3.05(2H,m),2.88-2.84(1H,m),2.62-2.54(3H,m),2.27-2.24(2H,m),1.43-1.41(9H,m) [0958] 1H NMR (CDCl3) δ8.33-8.28 (2H, m), 7.31-7.25 (1H, m) 5.79-5.78 (1H, m), 4.98-4.87 (1H, m), 4.84-4.73 (1H , m), 4.22-4.21 (1H, m), 3.93-3.91 (1H, m), 3.79-3.64 (3H, m), 3.62-3.56 (2H, m), 3.12-3.05 (2H, m), 2.88 -2.84 (1H, m), 2.62-2.54 (3H, m), 2.27-2.24 (2H, m), 1.43-1.41 (9H, m)

[0959] 质量(m/e)534(M+1-BOC) [0959] mass (m / e) 534 (M + 1-BOC)

[0960] 实施例35:合成1-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 35 [0960] Example: Synthesis of 1 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[0961] [0961]

[0962] 除了利用制备77获得的6.0mg(0.009mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得4.0mg标题化合物,收率74%。 [0962] Besides using 6.0mg (0.009mmol) {(1S) -1 obtained in Preparation 77 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2 - (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxo propyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22, to obtain 4.0mg of the title compound in 74% yield.

[0963] 1H NMR(CD3OD)δ8.31-8.28(2H,m),7.41-7.39(1H,m),4.96-4.85(2H,m),3.93-3.84(2H,m),3.80-3.74(2H,m),3.53-3.49(1H,m),3.47-3.44(2H,m),3.12(1H,brs),3.03(1H,brs),2.70-2.66(1H,m),2.58-2.52(3H,m),2.34-2.32(2H,m) [0963] 1H NMR (CD3OD) δ8.31-8.28 (2H, m), 7.41-7.39 (1H, m), 4.96-4.85 (2H, m), 3.93-3.84 (2H, m), 3.80-3.74 ( 2H, m), 3.53-3.49 (1H, m), 3.47-3.44 (2H, m), 3.12 (1H, brs), 3.03 (1H, brs), 2.70-2.66 (1H, m), 2.58-2.52 ( 3H, m), 2.34-2.32 (2H, m)

[0964] 质量(m/e)534(M+1) [0964] mass (m / e) 534 (M + 1)

[0965] 制备77:合成[(1S)-3-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [0965] Preparation 77: Synthesis of [(1S) -3- [2- (3,4- difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] carbamate - butyl

[0966] 除了利用制备55获得的6.3mg(0.020mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸和制备59获得的7.0mg(0.020mmol)2-(3,4-二氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得6.0m标题化合物,收率49%。 [0966] Besides using 6.3mg obtained in Preparation 55 (0.020mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 morpholin-4-yl] butanoic acid obtained and 7.0mg (0.020mmol) 2- (3,4- difluorophenyl) preparation 59 4- (trifluoromethyl) -5,6,7,8 tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45, the title compound is obtained 6.0m, 49% yield.

[0967] 1H NMR(CDCl3)δ8.32-8.24(2H,m),7.30-7.23(1H,m),5.84-5.79(1H,m),4.98-4.74(2H,m),4.24-4.19(2H,m),4.15-4.09(1H,m),3.94-3.84(2H,m),3.81(1H,brs),3.74-3.67(1H,m),3.66-3.46(1H,m),3.40-3.31(2H,m),3.12-3.00(2H,m),2.91-2.86(1H,m),2.63-2.57(1H,m),1.43-1.42(9H,m),1.28-1.24(3H,m) [0967] 1H NMR (CDCl3) δ8.32-8.24 (2H, m), 7.30-7.23 (1H, m), 5.84-5.79 (1H, m), 4.98-4.74 (2H, m), 4.24-4.19 ( 2H, m), 4.15-4.09 (1H, m), 3.94-3.84 (2H, m), 3.81 (1H, brs), 3.74-3.67 (1H, m), 3.66-3.46 (1H, m), 3.40- 3.31 (2H, m), 3.12-3.00 (2H, m), 2.91-2.86 (1H, m), 2.63-2.57 (1H, m), 1.43-1.42 (9H, m), 1.28-1.24 (3H, m )

[0968] 质量(m/e)514(M+1-BOC) [0968] mass (m / e) 514 (M + 1-BOC)

[0969] 实施例36:合成(6S)-4-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 [0969] Example 36: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5, 8- dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[0970] [0970]

[0971] 除了利用制备78获得的6.0mg(0.012mmol)[(1S)-3-[2-(3,4-二氟苯基)-4-(三氟)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得3.6mg标题化合物,收率56%。 [0971] Besides using 6.0mg (0.012mmol) [(1S) -3- [2- (3,4- difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyridine obtained in Preparation 78 and [3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo propyl] carbamic acid tert - butyl ester addition, in the same manner as Example 22, to obtain 3.6mg of the title compound in 56% yield.

[0972] 1H NMR(CD3OD)δ8.33-8.26(2H,m),7.45-7.38(1H,m),5.00-4.87(2H,m),4.18-4.11(2H,m),3.99-3.89(3H,m),3.66-3.55(2H,m),3.51-3.48(1H,m),3.38-3.29(2H,m),3.16(1H,brs),3.06(1H,brs),2.81-2.76(1H,m),2.69-2.61(1H,m),1.27-1.23(3H,m) [0972] 1H NMR (CD3OD) δ8.33-8.26 (2H, m), 7.45-7.38 (1H, m), 5.00-4.87 (2H, m), 4.18-4.11 (2H, m), 3.99-3.89 ( 3H, m), 3.66-3.55 (2H, m), 3.51-3.48 (1H, m), 3.38-3.29 (2H, m), 3.16 (1H, brs), 3.06 (1H, brs), 2.81-2.76 ( 1H, m), 2.69-2.61 (1H, m), 1.27-1.23 (3H, m)

[0973] 质量(m/e)514(M+1) [0973] mass (m / e) 514 (M + 1)

[0974] 制备79:合成[(1S)-3-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,3-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [0974] Preparation 79: Synthesis of [(1S) -3- [2- (3,4- difluorophenyl) -4- (trifluoromethyl) -5,3- dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamate - butyl

[0975] 除了利用制备51获得的44mg(0.139mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备59获得的49mg(0.139mmol)2-(3,4-二氟苯基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得82mg标题化合物,收率96%。 [0975] Preparation 51 except for using the obtained 44mg (0.139mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid obtained in preparation 59 and 49mg (0.139mmol) 2- (3,4- difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyridine and [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 82mg of the title compound in 96% yield.

[0976] 1H NMR(CDCl3)δ8.33-8.26(2H,m),7.32-7.25(1H,m),5.93-5.92(1H,m),5.00-4.90(1H,m),4.89-4.77(1H,m),4.22(1H,brs),3.96-3.93(1H,m),3.85-3.82(1H,m),3.76-3.55(2H,m),3.52-3.48(2H,m),3.42-3.38(1H,m),3.19-3.07(4H,m),2.92-2.87(1H,m),2.60-2.54(1H,m),2.47-2.29(2H,m),1.99-1.96(1H,m),1.90-1.83(1H,m),1.45-1.43(9H,m),1.02(3H,d,J=6.8Hz) [0976] 1H NMR (CDCl3) δ8.33-8.26 (2H, m), 7.32-7.25 (1H, m), 5.93-5.92 (1H, m), 5.00-4.90 (1H, m), 4.89-4.77 ( 1H, m), 4.22 (1H, brs), 3.96-3.93 (1H, m), 3.85-3.82 (1H, m), 3.76-3.55 (2H, m), 3.52-3.48 (2H, m), 3.42- 3.38 (1H, m), 3.19-3.07 (4H, m), 2.92-2.87 (1H, m), 2.60-2.54 (1H, m), 2.47-2.29 (2H, m), 1.99-1.96 (1H, m ), 1.90-1.83 (1H, m), 1.45-1.43 (9H, m), 1.02 (3H, d, J = 6.8Hz)

[0977] 质量(m/e)512(M+1-BOC) [0977] mass (m / e) 512 (M + 1-BOC)

[0978] 实施例37:合成(5R)-1-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [0978] Example 37: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5, 8- dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[0979] [0979]

[0980] 除了利用制备79获得的82mg(0.134mmol)[(1S)-3-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得58.3mg标题化合物,收率79%。 [0980] Preparation 79 except for using the obtained 82mg (0.134mmol) [(1S) -3- [2- (3,4- difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo oxopropyl] carbamic acid tert - butyl ester addition, in the same manner as Example 22 to obtain 58.3mg of the title compound in 79% yield.

[0981] 1H NMR(CD3OD)δ8.32-8.24(2H,m),7.45-7.37(1H,m),5.00-4.88(2H,m),3.98-3.95(1H,m),3.92-3.89(1H,m),3.79-3.76(1H,m),3.65-3.56(2H,m),3.42-3.37(1H,m),3.17-3.07(3H,m),2.93-2.87(1H,m),2.80-2.76(1H,m),2.44-2.36(2H,m),2.05-2.02(1H,m),1.88-1.85(1H,m),1.60-1.49(1H,m),1.06-1.04(3H,m) [0981] 1H NMR (CD3OD) δ8.32-8.24 (2H, m), 7.45-7.37 (1H, m), 5.00-4.88 (2H, m), 3.98-3.95 (1H, m), 3.92-3.89 ( 1H, m), 3.79-3.76 (1H, m), 3.65-3.56 (2H, m), 3.42-3.37 (1H, m), 3.17-3.07 (3H, m), 2.93-2.87 (1H, m), 2.80-2.76 (1H, m), 2.44-2.36 (2H, m), 2.05-2.02 (1H, m), 1.88-1.85 (1H, m), 1.60-1.49 (1H, m), 1.06-1.04 (3H , m)

[0982] 质量(m/e)512(M+1) [0982] mass (m / e) 512 (M + 1)

[0983] 制备80:合成{(1S)-3-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯 [0983] Preparation 80: Synthesis of {(1S) -3- [2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester

[0984] 除了利用制备51获得的112mg(0.357mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备62获得的100mg(0.325mmol)2-环戊基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得65mg标题化合物,收率84%。 [0984] Besides using 112mg (0.357mmol) (3S) -3 obtained in Preparation 51 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 100 mg (0.325 mmol) obtained in preparation 62 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d ] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give the title compound 65mg, yield 84%.

[0985] 1H NMR(CDCl3)δ5.88(1H,brs),4.88(1H,s),4.76-4.64(1H,m),4.18(1H,brs),3.88(1H,brs),3.77(1H,brs),3.63-3.47(2H,m),3.39-3.35(2H,m),3.01-2.97(3H,m),2.88-2.81(1H,m),2.55-2.30(3H,m),2.17-2.04(3H,m),1.93-1.85(6H,m),1.70(2H,brs),1.42-1.40(9H,m),1.00(3H,d,J=5.6Hz) [0985] 1H NMR (CDCl3) δ5.88 (1H, brs), 4.88 (1H, s), 4.76-4.64 (1H, m), 4.18 (1H, brs), 3.88 (1H, brs), 3.77 (1H , brs), 3.63-3.47 (2H, m), 3.39-3.35 (2H, m), 3.01-2.97 (3H, m), 2.88-2.81 (1H, m), 2.55-2.30 (3H, m), 2.17 -2.04 (3H, m), 1.93-1.85 (6H, m), 1.70 (2H, brs), 1.42-1.40 (9H, m), 1.00 (3H, d, J = 5.6Hz)

[0986] 质量(m/e)468(M+1-BOC) [0986] mass (m / e) 468 (M + 1-BOC)

[0987] 实施例38:合成(5R)-1-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [0987] Example 38: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[0988] [0988]

[0989] 除了利用制备80获得的176mg(0.310mmol){(1S)-1-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得120mg标题化合物,收率83%。 [0989] Besides using 176mg (0.310mmol) {(1S) -1- [2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyridine obtained in Preparation 80 and [3,4- d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - addition butyl ester, in the same manner as in Example 22, to obtain 120mg of the title compound in 83% yield.

[0990] 1H NMR(CD3OD)δ4.91-4.80(2H,m),4.15-4.11(1H,m),3.94-3.80(2H,m),3.75-3.67(1H,m),3.58-3.53(1H,m),3.44-3.37(2H,m),3.15-3.10(2H,m),3.01(1H,s),2.96-2.89(1H,m),2.81-2.72(1H,m),2.46-2.34(2H,m),2.12-2.03(3H,m),1.98-1.82(5H,m),1.79-1.73(2H,m),1.59-1.49(1H,m),1.05(3H,d,J=6.4Hz) [0990] 1H NMR (CD3OD) δ4.91-4.80 (2H, m), 4.15-4.11 (1H, m), 3.94-3.80 (2H, m), 3.75-3.67 (1H, m), 3.58-3.53 ( 1H, m), 3.44-3.37 (2H, m), 3.15-3.10 (2H, m), 3.01 (1H, s), 2.96-2.89 (1H, m), 2.81-2.72 (1H, m), 2.46- 2.34 (2H, m), 2.12-2.03 (3H, m), 1.98-1.82 (5H, m), 1.79-1.73 (2H, m), 1.59-1.49 (1H, m), 1.05 (3H, d, J = 6.4Hz)

[0991] 质量(m/e)468(M+1) [0991] mass (m / e) 468 (M + 1)

[0992] 制备81:合成[(1S)-3-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 Preparation of [0992] 81: Synthesis of [(1S) -3- [2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[0993] 除了利用制备55获得的113mg(0.357mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸和制备62获得的100mg(0.325mmol)2-环戊基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得180mg标题化合物,收率97%。 [0993] Preparation 55 except for using the obtained 113mg (0.357mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5-oxo it 4-yl] butanoic acid and 100 mg (0.325 mmol) obtained in preparation 62 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 180mg of the title compound in 97% yield.

[0994] 1H NMR(CDCl3)δ5.82-5.77(1H,m),4,89-4.78(1H,m),4.75-4.63(1H,m),4.31-4.19(2H,m),4.15-4.09(1H,m),3.94-3.84(2H,m),3.69(1H,brs),3.68-3.62(1H,m),3.54-3.45(1H,m),3.41-3.30(2H,m),3.09-2.98(2H,m),2.87-2.82(1H,m),2.60-2.51(1H,m),2.10-2.07(2H,m),1.97-1.85(5H,m),1.72-1.68(2H,brs),1.43-1.42(9H,m),1.28-1.24(3H,m) [0994] 1H NMR (CDCl3) δ5.82-5.77 (1H, m), 4,89-4.78 (1H, m), 4.75-4.63 (1H, m), 4.31-4.19 (2H, m), 4.15- 4.09 (1H, m), 3.94-3.84 (2H, m), 3.69 (1H, brs), 3.68-3.62 (1H, m), 3.54-3.45 (1H, m), 3.41-3.30 (2H, m), 3.09-2.98 (2H, m), 2.87-2.82 (1H, m), 2.60-2.51 (1H, m), 2.10-2.07 (2H, m), 1.97-1.85 (5H, m), 1.72-1.68 (2H , brs), 1.43-1.42 (9H, m), 1.28-1.24 (3H, m)

[0995] 质量(m/e)470(M+1) [0995] mass (m / e) 470 (M + 1)

[0996] 实施例39:合成(6S)-4-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 [0996] Example 39: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[0997] [0997]

[0998] 除了利用制备81获得的180mg(0.316mmol)[(1S)-3-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得117mg标题化合物,收率79%。 [0998] Besides using 180mg (0.316mmol) [(1S) -3- [2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyridine obtained in Preparation 81 and [3,4- d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] carbamate - addition butyl ester, in the same manner as in Example 22, to obtain 117mg of the title compound in 79% yield.

[0999] 1H NMR(CD3OD)δ4.83-4.78(2H,m),4.22-4.10(2H,m),4.00-3.81(3H,m),3.69-3.66(1H,m),3.59-3.47(2H,m),3.45-3.36(4H,m),3.10(1H,brs),3.00(1H,brs),2.82-2.76(1H,m),2.68-2.59(1H,m),2.12-2.10(2H,m),1.97-1.82(4H,m),1.79-1.73(1H,m),1.26(3H,d,J=6.0Hz) [0999] 1H NMR (CD3OD) δ4.83-4.78 (2H, m), 4.22-4.10 (2H, m), 4.00-3.81 (3H, m), 3.69-3.66 (1H, m), 3.59-3.47 ( 2H, m), 3.45-3.36 (4H, m), 3.10 (1H, brs), 3.00 (1H, brs), 2.82-2.76 (1H, m), 2.68-2.59 (1H, m), 2.12-2.10 ( 2H, m), 1.97-1.82 (4H, m), 1.79-1.73 (1H, m), 1.26 (3H, d, J = 6.0Hz)

[1000] 质量(m/e)470(M+1) [1000] mass (m / e) 470 (M + 1)

[1001] 制备82:合成{(1S)-3-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1001] Preparation 82: Synthesis of {(1S) -3- [2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1002] 除了利用制备57获得的120mg(0.357mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备62获得的100mg(0.325mmol)2-环戊基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得182mg标题化合物,收率95%。 [1002] Preparation 57 except for using the obtained 120mg (0.357mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butanoic acid obtained in preparation 62 and 100mg (0.325mmol) 2- cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride in the same manner as in preparation 45, to obtain 182mg of the title compound in 95% yield.

[1003] 1H NMR(CDCl3)δ4.78(1H,brs),4.87(1H,s),4.77-4.63(1H,m),4.20(1H,brs),3.89-3.86(1H,m),3.75-3.63(3H,m),3.60-3.53(2H,m),3.41-3.33(1H,m),3.05-2.98(2H,m),2.82-2.80(1H,m),2.60-2.51(3H,m),2.31-2.21(2H,m),2.10-2.07(2H,m),1.95-1.85(4H,m),1.75-1.70(2H,m),1.42-1.41(9H,m) [1003] 1H NMR (CDCl3) δ4.78 (1H, brs), 4.87 (1H, s), 4.77-4.63 (1H, m), 4.20 (1H, brs), 3.89-3.86 (1H, m), 3.75 -3.63 (3H, m), 3.60-3.53 (2H, m), 3.41-3.33 (1H, m), 3.05-2.98 (2H, m), 2.82-2.80 (1H, m), 2.60-2.51 (3H, m), 2.31-2.21 (2H, m), 2.10-2.07 (2H, m), 1.95-1.85 (4H, m), 1.75-1.70 (2H, m), 1.42-1.41 (9H, m)

[1004] 质量(m/e)490(M+1-BOC) [1004] mass (m / e) 490 (M + 1-BOC)

[1005] 实施例40:合成1-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1005] Example 40: Synthesis of 1 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1006] [1006]

[1007] 除了利用制备82获得的182mg(0.309mmol){(1S)-3-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以相同方式,获得105mg标题化合物,收率70%。 [1007] Besides using 182mg (0.309mmol) {(1S) -3- [2- cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyridine obtained in Preparation 82 and [3,4- d] pyrimidin -7 (6H) - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner to obtain the title compound 105mg, 70% yield.

[1008] 1H NMR(CD3OD)δ4.90-4.79(2H,m),3.93-3.77(4H,m),3.64-3.56(2H,m),3.49-3.37(2H,m),3.15(1H,brs),3.00(1H,brs),2.79-2.73(1H,m),2.66-2.52(3H,m),2.42-2.31(2H,m),2.12-2.08(2H,m),1.97-1.83(4H,m),1.79-1.73(2H,m), [1008] 1H NMR (CD3OD) δ4.90-4.79 (2H, m), 3.93-3.77 (4H, m), 3.64-3.56 (2H, m), 3.49-3.37 (2H, m), 3.15 (1H, brs), 3.00 (1H, brs), 2.79-2.73 (1H, m), 2.66-2.52 (3H, m), 2.42-2.31 (2H, m), 2.12-2.08 (2H, m), 1.97-1.83 ( 4H, m), 1.79-1.73 (2H, m),

[1009] 质量(m/e)490(M+1) [1009] mass (m / e) 490 (M + 1)

[1010] 制备83:合成3-氨基-4-羟基哌啶-1-羧酸叔-丁酯 [1010] Preparation 83: Synthesis of 3-amino-4-hydroxy-piperidine-1-carboxylic acid tert - butyl ester

[1011] (1)合成3,6-二羟基吡啶-1(2H)-羧酸叔-丁酯 [1011] (1) Synthesis of 3,6-dihydroxypyridine -1 (2H) - carboxylic acid tert - butyl ester

[1012] 将1g(12mmol)1,2,3,6-四羟基吡啶和2.76g(12.6mmol)二碳酸叔-丁酯溶解于40mL四氢呋喃/水(1∶1),搅拌5小时后,向其中加入100mL乙酸乙酯。 [1012] A 1g (12mmol) 1,2,3,6- tetrahydroxy-pyridine and 2.76g (12.6mmol) di-tert - butyl ester was dissolved in 40mL after tetrahydrofuran / water (1/1), stirred for 5 hours, 100mL of ethyl acetate was added thereto. 以水洗涤后,有机层用无水硫酸镁干燥。 After washing with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到2.1g(11.5mmol)标题化合物,收率91%。 The solvent was distilled off under reduced pressure, the residue was purified by column chromatography to give 2.1g (11.5mmol) of the title compound in 91% yield.

[1013] NMR:1H-NMR(CDCl3)δ5.81(1H,m),5.66(1H,m),3.88(2H,s),3.49(2H,t,J=6Hz),2.13(2h,brs),1.47(9H,s) [1013] NMR: 1H-NMR (CDCl3) δ5.81 (1H, m), 5.66 (1H, m), 3.88 (2H, s), 3.49 (2H, t, J = 6Hz), 2.13 (2h, brs ), 1.47 (9H, s)

[1014] (2)合成7-氧杂-3-氮杂双环[4.1.0]庚烷-3-羧酸叔-丁酯 [1014] (2) Synthesis of 7-oxa-3-azabicyclo [4.1.0] heptane-3-carboxylic acid tert - butyl ester

[1015] 将2.1g(11.5mmol)3,6-二羟基吡啶-1(2H)-羧酸叔-丁酯(步骤1的产物)和3.1g(12.6mmol)间-氯苯甲酸溶解于30mL二氯甲烷,搅拌5小时后,向其中加入100mL乙酸乙酯。 [1015] A 2.1g (11.5mmol) 3,6- dihydroxypyridine -1 (2H) - Inter-butyl ester (product of Step 1) and 3.1g (12.6mmol) - - t-chloro-benzoic acid was dissolved in 30mL dichloromethane, after stirring for 5 hours, and thereto was added 100mL of ethyl acetate. 以水洗涤后,有机层用无水硫酸镁干燥。 After washing with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到2.1g(10.5mmol)标题化合物,收率87%。 The solvent was distilled off, the residue was purified by column chromatography to give 2.1g (10.5mmol) of the title compound in a yield of 87% under reduced pressure.

[1016] 质量(m/e)200(M+1) [1016] mass (m / e) 200 (M + 1)

[1017] (3)合成叔-丁基-3-氨基-4-羟基哌啶-1-羧酸酯 [1017] (3) Synthesis of tert - butyl-3-amino-4-hydroxy-piperidine-1-carboxylate

[1018] 将2.9g(10.0mmol)7-氧杂-3-氮杂双环[4.1.0]庚烷-3-羧酸叔-丁酯(步骤2的产物)和1.2g(10.0mmol)(S)-1-苯基乙胺溶解于30mL水,回流搅拌12小时,然后向其中加入100mL乙酰乙酸乙酯。 [1018] A 2.9g (10.0mmol) 7- oxa-3-azabicyclo [4.1.0] heptane-3-carboxylic acid tert - butyl ester (product of step 2) and 1.2g (10.0mmol) ( S) -1- phenylethylamine was dissolved in 30mL of water, stirred at reflux for 12 hours and then thereto was added 100mL of ethyl acetoacetate. 反应混合物以水洗涤后,有机层用无水硫酸镁干燥。 The reaction mixture was washed with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,所得溶液溶解于甲醇。 The solvent was distilled off under reduced pressure, and the resulting solution was dissolved in methanol. 反应利用120mg 20%钯/碳,在氢气氛下进行9小时,溶剂经Cellite过滤。 The reaction using 120mg 20% ​​palladium / carbon under a hydrogen atmosphere for 9 hours, the solvent was filtered through Cellite. 减压下蒸馏掉滤液,然后残留物通过柱层析纯化,得到0.50g(2.3mmol)标题化合物,收率23%。 The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography to give 0.50g (2.3mmol) of the title compound in 23% yield.

[1019] 质量(m/e)217(M+1) [1019] mass (m / e) 217 ​​(M + 1)

[1020] 制备84:合成2-[4-(三氟甲基)苯基]-4,5,6,7-四氢[1,3]噻唑并[4,5-c]吡啶氢氯化物 [1020] Preparation 84: Synthesis of 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine hydrochloride

[1021] (1)合成4-羟基-3-{[4-(三氟甲基)苯甲酰]氨基}哌啶-1-羧酸叔-丁酯 [1021] (1) Synthesis of 4-hydroxy-3 - {[4- (trifluoromethyl) benzoyl] amino} piperidine-1-carboxylic acid tert - butyl ester

[1022] 将0.50g(2.3mmol)3-氨基-4-羟基哌啶-1-羧酸叔-丁酯(制备83的产物)和0.32mL(2.3mmol)三乙胺溶解于30mL二氯甲烷,并向其中滴加0.34mL(2.3mmol)4-三氟甲基苯甲酰氯,同时0℃下搅拌1小时,接着加入100mL乙酰乙酸乙酯,然后以水洗涤。 [1022] A 0.50g (2.3mmol) 3- amino-4-hydroxy-piperidine-1-carboxylic acid tert - butyl ester (the product of Preparation 83) and 0.32 mL (2.3 mmol) of triethylamine were dissolved in 30mL dichloromethane , and thereto was added dropwise 0.34mL (2.3mmol) 4- trifluoromethylbenzoyl chloride, while stirring at 0 ℃ 1 hour, followed by addition of 100mL of ethyl acetoacetate, and then washed with water. 有机层用无水硫酸镁干燥。 The organic layer was dried over anhydrous magnesium sulfate. 反应液过滤,并在减压下蒸馏,残留物通过柱层析纯化,得到0.48g(1.2mmol)标题化合物,总收率54%。 The reaction was filtered, and distilled under reduced pressure, the residue was purified by column chromatography to give 0.48g (1.2mmol) of the title compound in a total yield of 54%.

[1023] 质量(m/e)335(M+1) [1023] mass (m / e) 335 (M + 1)

[1024] (2)合成4-氧代-3-{[4-(三氟甲基)苯甲酰]氨基}哌啶-1-羧酸叔-丁酯 [1024] (2) Synthesis of 4-oxo-3 - {[4- (trifluoromethyl) benzoyl] amino} piperidine-1-carboxylic acid tert - butyl ester

[1025] 将0.48g(1.2mmol)4-羟基-3-{[4-(三氟甲基)苯甲酰]氨基}哌啶-1-羧酸叔-丁酯(步骤1的产物)溶解于10mL二氯甲烷,并向其中滴加5.24g(1.9mmol)Dess-Martin试剂。 [1025] A 0.48g (1.2mmol) 4- hydroxy-3 - {[4- (trifluoromethyl) benzoyl] amino} piperidine-1-carboxylic acid tert - butyl ester (product of step 1) was dissolved in 10mL of dichloromethane, and a solution of 5.24g (1.9mmol) Dess-Martin reagent. 搅拌5小时后,其中滴加50mL乙酰乙酸乙酯,所得溶液以水洗涤。 After stirring for 5 hours, 50mL of ethyl acetoacetate was added dropwise, the resulting solution was washed with water. 有机层用无水硫酸镁干燥。 The organic layer was dried over anhydrous magnesium sulfate. 反应液过滤,减压下蒸馏,残留物通过柱层析纯化,得到0.30g(0.78mmol)标题化合物,总收率65%。 The reaction solution was filtered, distilled under reduced pressure, the residue was purified by column chromatography to give 0.30g (0.78mmol) of the title compound, total yield 65%.

[1026] NMR:1H-NMR(CDCl3)δ7.94(2H,d,J=8Hz),7.73(2H,d,J=8Hz),7.16(1H,brs),5.05~5.00(1H,m),4.70~4.60(1H,m),4.55~4.45(1H,m),3.12~3.00(1H,m),2.77~2.66(2H,m),2.61~2.57(2H,m),1.55(9H,s) [1026] NMR: 1H-NMR (CDCl3) δ7.94 (2H, d, J = 8Hz), 7.73 (2H, d, J = 8Hz), 7.16 (1H, brs), 5.05 ~ 5.00 (1H, m) , 4.70 ~ 4.60 (1H, m), 4.55 ~ 4.45 (1H, m), 3.12 ~ 3.00 (1H, m), 2.77 ~ 2.66 (2H, m), 2.61 ~ 2.57 (2H, m), 1.55 (9H, s)

[1027] 质量(m/e)387(M+1) [1027] mass (m / e) 387 (M + 1)

[1028] (3)合成2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5-c]吡啶-5(4H)-羧酸叔-丁酯 [1028] (3) Synthesis of 2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5-c] pyridin -5 (4H) - carboxylic acid tert - butyl ester

[1029] 将0.40g(1.0mmol)4-氧代-3-{[4-(三氟甲基)苯甲酰]氨基}哌啶-1-羧酸叔-丁酯(步骤2的产物)溶解于0.47g(1.2mmol)Lawesson氏试剂,所得溶液在30mL甲苯回流下搅拌4小时,减压下蒸馏。 [1029] A 0.40g (1.0mmol) 4- oxo-3 - {[4- (trifluoromethyl) benzoyl] amino} piperidine-1-carboxylic acid tert - (product of step 2) Butyl Lawesson's reagent was dissolved, the resulting solution was stirred for 4 hours at reflux in 30mL toluene 0.47g (1.2mmol), distilled under reduced pressure. 残留物通过柱层析纯化,得到0.30g(0.91mmol)标题化合物,总收率91%。 The residue was purified by column chromatography to give 0.30g (0.91mmol) of the title compound in a total yield of 91%.

[1030] NMR:1H-NMR(CDCl3)δ8.00(2H,d,J=8Hz),7.68(2H,d,J=8Hz),4.70(2H,s),3.79(2H,s),2.93(2H,m),1.50(9H,s) [1030] NMR: 1H-NMR (CDCl3) δ8.00 (2H, d, J = 8Hz), 7.68 (2H, d, J = 8Hz), 4.70 (2H, s), 3.79 (2H, s), 2.93 (2H, m), 1.50 (9H, s)

[1031] 质量(m/e)331(M+1) [1031] mass (m / e) 331 (M + 1)

[1032] (4)合成2-[4-(三氟甲基)苯基]-4,5,6,7-四氢[1,3]噻唑并[4.5-c]吡啶氢氯化物 [1032] (4) Synthesis of 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4.5-c] pyridine hydrochloride

[1033] 将0.30g(0.91mmol)2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5-c]吡啶-5(4H)-羧酸叔-丁酯(步骤3的产物)溶解于15mL 4.0M HCl/二噁烷溶液,接着搅拌2小时。 [1033] A 0.30g (0.91mmol) 2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5-c] pyridin -5 (4H ) - carboxylic acid tert - butyl ester the product (step 3) was dissolved in 15mL 4.0M HCl / dioxane solution, followed by stirring for 2 hours. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到0.15g(0.53mmol)标题化合物,收率58%。 The solvent was distilled off, the residue was purified by column chromatography to give 0.15g (0.53mmol) of the title compound in a yield of 58% under reduced pressure.

[1034] NMR:1H-NMR(CD3OD)δ8.08(2H,d,J=8Hz),7.77(2H,d,J=8Hz),4.03(2H,s),3.16(2H,t,J=6Hz),2.96(2H,m) [1034] NMR: 1H-NMR (CD3OD) δ8.08 (2H, d, J = 8Hz), 7.77 (2H, d, J = 8Hz), 4.03 (2H, s), 3.16 (2H, t, J = 6Hz), 2.96 (2H, m)

[1035] 质量(m/e)285(M+1) [1035] mass (m / e) 285 (M + 1)

[1036] 制备88:合成[(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丙基]氨基甲酸叔-丁酯 [1036] Preparation 88: Synthesis of [(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl} propyl] carbamic acid tert - butyl ester

[1037] 以制备45的相同方式,将制备51获得的30.0mg(0.095mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-甲基-2-氧代哌啶-1-基]-丁酸和制备68获得的30.0mg(0.095mmol)2-[4-(三氟甲基)苯基]-4,5,6,7-四氢[1,3]噻唑并[4,5-c]吡啶反应,得到30mg标题化合物,收率13%。 [1037] In the same manner as in Preparation 45, the preparation obtained in 51 30.0mg (0.095mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) - methyl-2 - oxo-piperidin-1-yl] - butanoic acid obtained in preparation 68 and 30.0mg (0.095mmol) 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [ 1,3] thiazolo [4,5-c] pyridine, to give 30mg of the title compound in 13% yield.

[1038] NMR:1H-NMR(CDCl3)δ8.00(2H,m),7.69(2H,m),5.84(1H,m),4.84(1H,s),4.70(1H,m),4.22(1H,m),4.03~3.89(1H,m),3.81(1H,t,J=6hz),3.65(1H,m),3.52(2H,m),3.36(1H,m),3.10~2.80(4H,m),2.55~2.35(3H,m),1.95(1H,m),1.80(1H,m),1.42(9H,s),1.00(3H,m) [1038] NMR: 1H-NMR (CDCl3) δ8.00 (2H, m), 7.69 (2H, m), 5.84 (1H, m), 4.84 (1H, s), 4.70 (1H, m), 4.22 ( 1H, m), 4.03 ~ 3.89 (1H, m), 3.81 (1H, t, J = 6hz), 3.65 (1H, m), 3.52 (2H, m), 3.36 (1H, m), 3.10 ~ 2.80 ( 4H, m), 2.55 ~ 2.35 (3H, m), 1.95 (1H, m), 1.80 (1H, m), 1.42 (9H, s), 1.00 (3H, m)

[1039] 质量(m/e)581(M+1) [1039] mass (m / e) 581 (M + 1)

[1040] 实施例41:合成(5R)-1-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-5-甲基哌啶-2-酮 [1040] Example 41: Synthesis of (5R) -1 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7 dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl} butyl] -5-methyl-piperidin-2-one

[1041] [1041]

[1042] 以实施例3的相同方式,利用制备85获得的5mg(0.0086mmol)[(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丙基]氨基甲酸叔-丁酯,获得1.2mg标题化合物,总收率29%。 [1042] In the same manner as Example 3, prepared using 85 5mg (0.0086mmol) obtained in [(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine-5 (4H) - yl} propyl] carbamic acid tert - butyl ester, the title compound 1.2mg, 29% overall yield.

[1043] NMR:1H-NMR(CD3OD)δ8.12(2H,d,J=8Hz),7.80(2H,d,J=8Hz),4.85(1H,s),4.79(1H,s),4.03(1H,t,J=6Hz),3.89(2H,m),3.79(1H,m),3.55(1H,m),3.36(1H,m),3.13(2H,m),2.98(2H,m),2.81(1H,m),2.42(2H,m),2.03(1H,m),1.86(1H,m),1.53(9H,s),1.05(3H,d,J=7Hz) [1043] NMR: 1H-NMR (CD3OD) δ8.12 (2H, d, J = 8Hz), 7.80 (2H, d, J = 8Hz), 4.85 (1H, s), 4.79 (1H, s), 4.03 (1H, t, J = 6Hz), 3.89 (2H, m), 3.79 (1H, m), 3.55 (1H, m), 3.36 (1H, m), 3.13 (2H, m), 2.98 (2H, m ), 2.81 (1H, m), 2.42 (2H, m), 2.03 (1H, m), 1.86 (1H, m), 1.53 (9H, s), 1.05 (3H, d, J = 7Hz)

[1044] 质量(m/e)481(M+1) [1044] mass (m / e) 481 (M + 1)

[1045] 实施例42:合成(6S)-4-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-6-甲基吗啉-3-酮 [1045] Example 42: Synthesis of (6S) -4 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7 dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl} butyl] -6-methyl-morpholin-3-one

[1046] [1046]

[1047] 除了利用制备84获得的45mg(0.14mmol)2-[4-(三氟甲基)苯基]-4,5,6,7-四氢[1,3]噻唑并[4,5-c]吡啶和制备55获得的45mg(0.14mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸之外,依次以制备45和实施例3的相同方式,获得29mg标题化合物,收率43%。 [1047] Preparation 84 except for using the obtained 45mg (0.14mmol) 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5 -C] pyridine obtained in preparation 55 and 45mg (0.14mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5-oxo it 4-yl] butanoic acid addition, and 45 are sequentially prepared in the same manner as Example 3, to obtain 29mg of the title compound in 43% yield.

[1048] NMR:1H-NMR(CD3OD)δ8.12(2H,d,J=8Hz),7.79(2H,d,J=8Hz),4.85(1H,s),4.79(1H,s),4.20(2H,m),4.02(1H,t,J=6Hz),3.98(1H,m),3.90(1H,M),3.88(1H,m),3.72(1H,m),3.60(1H,m),3.38(2H,m),3.09(1H,m),2.99(1H,m),2.96(1H,m),2.77(1H,m),1.26(3H,d,J=6Hz) [1048] NMR: 1H-NMR (CD3OD) δ8.12 (2H, d, J = 8Hz), 7.79 (2H, d, J = 8Hz), 4.85 (1H, s), 4.79 (1H, s), 4.20 (2H, m), 4.02 (1H, t, J = 6Hz), 3.98 (1H, m), 3.90 (1H, m), 3.88 (1H, m), 3.72 (1H, m), 3.60 (1H, m ), 3.38 (2H, m), 3.09 (1H, m), 2.99 (1H, m), 2.96 (1H, m), 2.77 (1H, m), 1.26 (3H, d, J = 6Hz)

[1049] 质量(m/e)483(M+1) [1049] mass (m / e) 483 (M + 1)

[1050] 实施例43:合成1-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-5,5-二氟哌啶-2-酮 [1050] Example 43: Synthesis of 1 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1 , 3] thiazolo [4,5, c] pyridin -5 (4H) - yl} butyl] -5,5-difluoropiperidin-2-one

[1051] [1051]

[1052] 除了利用制备84获得的45mg(0.14mmol)2-[4-(三氟甲基)苯基]-4,5,6,7-四氢[1,3]噻唑并[4,5-c]吡啶和制备57获得的47mg(0.14mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸之外,依次以制备45和实施例3的相同方式,获得45mg标题化合物,收率64%。 [1052] Preparation 84 except for using the obtained 45mg (0.14mmol) 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5 -C] pyridine prepared and obtained in 57 47mg (0.14mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butanoic acid addition, 45 was prepared in the same manner successively and Example 3, to obtain 45mg of the title compound in 64% yield.

[1053] NMR:1H-NMR(CD3OD)δ8.12(2H,d,J=8Hz),7.79(2H,d,J=8Hz),4.85(1H,s),4.79(1H,s),4.02(1H,t,J=6Hz),3.90(2H,m),3.81(3H,m),3.50(1H,m),3.09(1H,m),3.00(1H,m),2.91(1H,m),2.62(2H,m),2.37(2H,m) [1053] NMR: 1H-NMR (CD3OD) δ8.12 (2H, d, J = 8Hz), 7.79 (2H, d, J = 8Hz), 4.85 (1H, s), 4.79 (1H, s), 4.02 (1H, t, J = 6Hz), 3.90 (2H, m), 3.81 (3H, m), 3.50 (1H, m), 3.09 (1H, m), 3.00 (1H, m), 2.91 (1H, m ), 2.62 (2H, m), 2.37 (2H, m)

[1054] 质量(m/e)503(M+1) [1054] mass (m / e) 503 (M + 1)

[1055] 制备89:合成2-(4-氟苯基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶氢氯化物 [1055] Preparation 89: Synthesis of 2- (4-fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine hydrochloride

[1056] 除了利用制备83获得的0.20g(0.92mmol)叔-丁基-3-氨基-4-羟基哌啶-1-羧酸酯和0.11mL(0.92mmol)4-氟苯甲酰氯之外,以制备84的相同方式,获得70mg标题化合物,收率32%。 [1056] Preparation 83 except for using the obtained 0.20g (0.92 mmol) tert - butyl-3-amino-4-hydroxy-piperidine-1-carboxylate, and 0.11mL (0.92mmol) 4- fluorobenzoyl chloride addition , 84 was prepared in the same manner to obtain 70mg of the title compound in 32% yield.

[1057] NMR:1H-NMR(CD3OD)δ7.90(2H,m),7.20(2H,m),4.98(2H,s),3.13(2H,t,J=6Hz),2.89(2H,m) [1057] NMR: 1H-NMR (CD3OD) δ7.90 (2H, m), 7.20 (2H, m), 4.98 (2H, s), 3.13 (2H, t, J = 6Hz), 2.89 (2H, m )

[1058] 质量(m/e)235(M+1) [1058] mass (m / e) 235 (M + 1)

[1059] 实施例44:合成(5R)-1-{(2S)-2-氨基-4-[2-(4-氟苯基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 44 [1059] Example: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [ 4,5, c] pyridin -5 (4H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1060] [1060]

[1061] 除了利用制备86获得的10mg(0.037mmol)2-(4-氟苯基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备51获得的12.0mg(0.037mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-甲基-2-氧代哌啶-1-基]-丁酸之外,依次以制备45和实施例3的相同方式,获得5.8mg标题化合物,收率36%。 [1061] Besides using 10mg (0.037mmol) 2- (4- fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazole obtained in Preparation 86 and [4,5, c] pyridine and preparation 51 12.0mg (0.037mmol) obtained from (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) - methyl-2-oxo-piperidin-1-yl] - acid addition, and 45 are sequentially prepared in the same manner as Example 3, to obtain 5.8mg of the title compound in 36% yield.

[1062] NMR:1H-NMR(CD3OD)δ7.92(2H,m),7.20(2H,m),4.78(1H,s),4.71(1H,s),3.98(1H,m),3.89(2H,m),3.71(1H,m),3.51(1H,m),3.36(1H,m),3.13(2H,m),2.98(2H,m),2.80(1H,m),2.38(2H,m),1.98(1H,m),1.82(1H,m),1.50(9H,s),1.00(3H,m) [1062] NMR: 1H-NMR (CD3OD) δ7.92 (2H, m), 7.20 (2H, m), 4.78 (1H, s), 4.71 (1H, s), 3.98 (1H, m), 3.89 ( 2H, m), 3.71 (1H, m), 3.51 (1H, m), 3.36 (1H, m), 3.13 (2H, m), 2.98 (2H, m), 2.80 (1H, m), 2.38 (2H , m), 1.98 (1H, m), 1.82 (1H, m), 1.50 (9H, s), 1.00 (3H, m)

[1063] 质量(m/e)431(M+1) [1063] mass (m / e) 431 (M + 1)

[1064] 实施例45:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(4-氟苯基)6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮 [1064] Example 45: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (4-fluorophenyl) 6,7-dihydro [1,3 ] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methylmorpholine-3-one

[1065] [1065]

[1066] 除了利用制备86获得的10mg(0.037mmol)2-(4-氟苯基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备55获得的12.0mg(0.037mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸之外,依次以制备45和实施例3的相同方式,获得5.0mg标题化合物,收率31%。 [1066] Besides using 10mg (0.037mmol) 2- (4- fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazole obtained in Preparation 86 and [4,5, c] pyridine and preparation 55 12.0mg (0.037mmol) (3S) -3 obtained - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5-oxo-morpholin-4 yl] butanoic acid addition, and 45 are sequentially prepared in the same manner as Example 3, to obtain 5.0mg of the title compound in 31% yield.

[1067] NMR:1H-NMR(CD3OD)δ7.91(2H,m),7.18(2H,m),4.78(1H,s),4.71(1H,s),4.15(2H,m),4.02(1H,t,J=6Hz),3.91(2H,m),3.81(2H,M),3.70(1H,m),3.65(2H,m),3.55(1H,m),3.00(2H,m),2.93(1H,m),2.80(1H,m),1.22(3H,m) [1067] NMR: 1H-NMR (CD3OD) δ7.91 (2H, m), 7.18 (2H, m), 4.78 (1H, s), 4.71 (1H, s), 4.15 (2H, m), 4.02 ( 1H, t, J = 6Hz), 3.91 (2H, m), 3.81 (2H, m), 3.70 (1H, m), 3.65 (2H, m), 3.55 (1H, m), 3.00 (2H, m) , 2.93 (1H, m), 2.80 (1H, m), 1.22 (3H, m)

[1068] 质量(m/e)433(M+1) [1068] mass (m / e) 433 (M + 1)

[1069] 实施例46:合成1-{(2S)-2-氨基-4-[2-(4-氟苯基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1069] Example 46: Synthesis of 1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1070] [1070]

[1071] 除了利用制备86获得的10mg(0.037mmol)2-(4-氟苯基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备57获得的14.0mg(0.037mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸之外,依次以制备45和实施例3的相同方式,获得8.0mg标题化合物,收率48%。 [1071] Besides using 10mg (0.037mmol) 2- (4- fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazole obtained in Preparation 86 and [4,5, c] pyridine and preparation 57 14.0mg (0.037mmol) (3S) -3 obtained - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin-1-yl) butyrate acid addition, and 45 are sequentially prepared in the same manner as Example 3, to obtain 8.0mg of the title compound in 48% yield.

[1072] NMR:1H-NMR(CD3OD)δ7.91(2H,dm),7.20(2H,m),4.79(1H,s),4.71(1H,s),3.95(1H,m),3.90(3H,m),3.82(2H,m),3.45(1H,m),3.00(2H,m),2.92(1H,m),2.80(1H,m),2.59(2H,m),2.34(2H,m) [1072] NMR: 1H-NMR (CD3OD) δ7.91 (2H, dm), 7.20 (2H, m), 4.79 (1H, s), 4.71 (1H, s), 3.95 (1H, m), 3.90 ( 3H, m), 3.82 (2H, m), 3.45 (1H, m), 3.00 (2H, m), 2.92 (1H, m), 2.80 (1H, m), 2.59 (2H, m), 2.34 (2H , m)

[1073] 质量(m/e)453(M+1) [1073] mass (m / e) 453 (M + 1)

[1074] 制备87:合成2-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶 [1074] Preparation 87: Synthesis of 2- (tetrahydro -2H- pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine

[1075] 除了利用制备83获得的0.22g(1.0mmol)3-氨基-4-羟基哌啶-1-羧酸叔-丁酯和(1.0mmol)四氢-2H-吡喃-4-碳酰氯0.15mg之外,以制备45的相同方式,获得45mg标题化合物,收率17%。 [1075] Preparation 83 except for using the obtained 0.22g (1.0mmol) 3- amino-4-hydroxy-piperidine-1-carboxylic acid tert - butyl ester and (1.0 mmol) tetrahydro -2H- pyran-4-carbonyl chloride 0.15mg addition, in the same manner as in preparation 45 to give the title compound 45mg, 17% yield.

[1076] 质量(m/e)225(M+1) [1076] mass (m / e) 225 (M + 1)

[1077] 实施例47:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5-甲基哌啶-2-酮 [1077] Example 47: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7 - dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -5-methyl-piperidin-2-one

[1078] [1078]

[1079] 除了利用制备87获得的8.0mg(0.031mmol)2-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备51获得的9.6mg(0.031mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-甲基-2-氧代哌啶-1-基]-丁酸之外,依次以制备45和实施例42的相同方式,获得3.2mg标题化合物,收率25%。 [1079] Besides using 8.0mg obtained in Preparation 87 (0.031mmol) 2- (tetrahydro -2H- pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4 , 5, c] pyridine obtained in preparation 51 and 9.6mg (0.031mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) - methyl-2-oxopiperidine l-yl] - butyric acid addition, and 45 are sequentially prepared in the same manner as Example 42, to obtain 3.2mg of the title compound in a yield of 25%.

[1080] NMR:1H-NMR(CD3OD)δ4.73(1H,s),4.65(1H,s),4.03(2H,m),3.96(1H,t,J=6Hz),3.83(2H,m),3.76(1H,m),3.69(1H,m),3.60(3H,m),3.52(1H,m),3.35(1H,m),3.25(1H,m),3.11(1H,m),2.97(1H,m),2.88(2H,m),2.75(1H,m),2.43(2H,m),1.99(2H,m),1.85(2H,m),1.55(1H,m),1.05(3H,d,J=7Hz) [1080] NMR: 1H-NMR (CD3OD) δ4.73 (1H, s), 4.65 (1H, s), 4.03 (2H, m), 3.96 (1H, t, J = 6Hz), 3.83 (2H, m ), 3.76 (1H, m), 3.69 (1H, m), 3.60 (3H, m), 3.52 (1H, m), 3.35 (1H, m), 3.25 (1H, m), 3.11 (1H, m) , 2.97 (1H, m), 2.88 (2H, m), 2.75 (1H, m), 2.43 (2H, m), 1.99 (2H, m), 1.85 (2H, m), 1.55 (1H, m), 1.05 (3H, d, J = 7Hz)

[1081] 质量(m/e)421(M+1) [1081] mass (m / e) 421 (M + 1)

[1082] 实施例48:合成(6S)-4-{(2R)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮 [1082] Example 48: Synthesis of (6S) -4 - {(2R) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7 - dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methylmorpholine-3-one

[1083] [1083]

[1084] 除了利用制备87获得的8.0mg(0.031mmol)2-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备55获得的10mg(0.031mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸之外,依次以制备45和实施例42的相同方式,获得2.5mg标题化合物,收率19%。 [1084] Besides using 8.0mg obtained in Preparation 87 (0.031mmol) 2- (tetrahydro -2H- pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4 , 5, c] pyridine obtained in preparation 55 and 10mg (0.031mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 substituting morpholin-4-yl] butanoic acid addition, and 45 are sequentially prepared in the same manner as Example 42, to obtain 2.5mg of the title compound in a yield of 19%.

[1085] NMR:1H-NMR(CD3OD)δ4.88(1H,s),4.66(1H,s),4.21(2H,m),4.05(2H,m),3.95(2H,m),3.83(1H,m),3.75(1H,m),3.58(4H,m),3.36(2H,m),3.25(1H,m),2.97(1H,m),2.86(2H,m),2.68(1H,m),2.00(2H,m),1.85(2H,m),1.26(3H,d,J=7Hz) [1085] NMR: 1H-NMR (CD3OD) δ4.88 (1H, s), 4.66 (1H, s), 4.21 (2H, m), 4.05 (2H, m), 3.95 (2H, m), 3.83 ( 1H, m), 3.75 (1H, m), 3.58 (4H, m), 3.36 (2H, m), 3.25 (1H, m), 2.97 (1H, m), 2.86 (2H, m), 2.68 (1H , m), 2.00 (2H, m), 1.85 (2H, m), 1.26 (3H, d, J = 7Hz)

[1086] 质量(m/e)423(M+1) [1086] mass (m / e) 423 (M + 1)

[1087] 实施例49:合成1-{(2S)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-67-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5,5-二氟哌啶-2-酮 [1087] Example 49: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -67- dihydro [1, 3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1088] [1088]

[1089] 除了利用制备87获得的8.0mg(0.031mmol)2-(四氢-2H-吡喃-4-基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备57获得的10mg(0.031mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸之外,依次以制备45和实施例3的相同方式,获得3.6mg标题化合物,收率26%。 [1089] Besides using 8.0mg obtained in Preparation 87 (0.031mmol) 2- (tetrahydro -2H- pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4 , 5, c] pyridine was prepared and 57 10mg (0.031mmol) (3S) -3 obtained - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidine 1-yl) butanoic acid addition sequentially prepared in the same manner as in Example 45 and 3 embodiment, to obtain 3.6mg of the title compound, yield 26%.

[1090] NMR:1H-NMR(CD3OD)δ4.88(1H,s),4.73(1H,s),4.03(2H,m),3.95(1H,t,J=6Hz),3.83(2H,m),3.77(3H,m),3.58(2H,m),3.48(1H,m),3.25(1H,m),2.97(1H,m),2.88(2H,m),2.70(1H,m),2.61(2H,m),2.37(2H,m),2.01(2H,m),1.85(2H,m) [1090] NMR: 1H-NMR (CD3OD) δ4.88 (1H, s), 4.73 (1H, s), 4.03 (2H, m), 3.95 (1H, t, J = 6Hz), 3.83 (2H, m ), 3.77 (3H, m), 3.58 (2H, m), 3.48 (1H, m), 3.25 (1H, m), 2.97 (1H, m), 2.88 (2H, m), 2.70 (1H, m) , 2.61 (2H, m), 2.37 (2H, m), 2.01 (2H, m), 1.85 (2H, m)

[1091] 质量(m/e)443(M+1) [1091] mass (m / e) 443 (M + 1)

[1092] 制备88:合成2-(三氟甲基)4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶 [1092] Preparation 88: Synthesis of 2- (trifluoromethyl) 4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine

[1093] 除了利用制备83获得的0.30g(1.4mmol)3-氨基-4-羟基哌啶-1-羧酸叔-丁酯和0.19mL(1.4mmol)三氟乙酸酐之外,以制备84的相同方式,获得20mg标题化合物,收率9.3%。 [1093] Preparation 83 except for using the obtained 0.30g (1.4mmol) 3- amino-4-hydroxy-piperidine-1-carboxylic acid tert - butyl ester and 0.19 mL (1.4 mmol) of trifluoroacetic anhydride addition, to prepare a 84 in the same manner to obtain 20mg of the title compound in a yield of 9.3%.

[1094] NMR:1H-NMR(CDCl3)δ4.52(2H,brs),3.64(2H,brs),3.41(2H,brs) [1094] NMR: 1H-NMR (CDCl3) δ4.52 (2H, brs), 3.64 (2H, brs), 3.41 (2H, brs)

[1095] 质量(m/e)209(M+1) [1095] mass (m / e) 209 (M + 1)

[1096] 实施例50:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(三氟甲基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮 [1096] Example 50: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3 ] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methylmorpholine-3-one

[1097] [1097]

[1098] 除了利用制备88获得的5.0mg(0.032mmol)2-(三氟甲基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备55获得的11mg(0.032mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]丁酸之外,依次以制备45和实施例3的相同方式,获得2.0mg标题化合物,收率15%。 [1098] Besides using 5.0mg (0.032mmol) 2- (trifluoromethyl) -4,5,6,7-tetrahydro [1,3] thiazole obtained in Preparation 88 and [4,5, c] pyridine and 11mg (0.032mmol) (3S) obtained in preparation 55 3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5-oxo-morpholin-4-yl ] butanoic acid addition, and 45 are sequentially prepared in the same manner as Example 3, to obtain 2.0mg of the title compound in 15% yield.

[1099] NMR:1H-NMR(CD3OD)δ4.80(1H,s),4.75(1H,s),4.11(3H,m),3.95(2H,m),3.85(2H,m),3.80(1H,m),3.67(1H,m),3.56(2H,m),3.08(1H,m),2.99(1H,m),2.89(1H,m),2.72(1H,m) [1099] NMR: 1H-NMR (CD3OD) δ4.80 (1H, s), 4.75 (1H, s), 4.11 (3H, m), 3.95 (2H, m), 3.85 (2H, m), 3.80 ( 1H, m), 3.67 (1H, m), 3.56 (2H, m), 3.08 (1H, m), 2.99 (1H, m), 2.89 (1H, m), 2.72 (1H, m)

[1100] 质量(m/e)407(M+1) [1100] mass (m / e) 407 (M + 1)

[1101] 实施例51:合成1-{(2S)-2-氨基-4-氧代-4-[2-(三氟甲基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5,5-二氟哌啶-2-酮 [1101] Example 51: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [ 4,5, c] pyridin -5 (4H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1102] [1102]

[1103] 除了利用制备88获得的5.0mg(0.032mmol)2-(三氟甲基)-4,5,6,7-四氢[1,3]噻唑并[4,5,c]吡啶和制备57获得的11mg(0.032mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸之外,依次以制备45和实施例3的相同方式,获得3.0mg标题化合物,收率22%。 [1103] Besides using 5.0mg (0.032mmol) 2- (trifluoromethyl) -4,5,6,7-tetrahydro [1,3] thiazole obtained in Preparation 88 and [4,5, c] pyridine and preparation 57 11mg (0.032mmol) (3S) -3 obtained - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin-1-yl) butanoic acid addition, and 45 are sequentially prepared in the same manner as Example 3, to obtain 3.0mg of the title compound in a yield of 22%.

[1104] NMR:1H-NMR(CD3OD)δ4.82(1H,s),4.75(1H,s),3.96(1H,t,J=6Hz),3.85(2H,m),3.80(1H,m),3.72(2H,m),3.45(1H,m),3.08(1H,m),2.99(1H,m),2.85(1H,m),2.72(1H,m),2.57(2H,m),2.33(2H,m) [1104] NMR: 1H-NMR (CD3OD) δ4.82 (1H, s), 4.75 (1H, s), 3.96 (1H, t, J = 6Hz), 3.85 (2H, m), 3.80 (1H, m ), 3.72 (2H, m), 3.45 (1H, m), 3.08 (1H, m), 2.99 (1H, m), 2.85 (1H, m), 2.72 (1H, m), 2.57 (2H, m) , 2.33 (2H, m)

[1105] 质量(m/e)427(M+1) [1105] mass (m / e) 427 (M + 1)

[1106] 制备89:合成2-(2-甲氧基乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1106] Preparation 89: Synthesis of 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride salt

[1107] (1)合成3-甲氧基丙烷酰亚胺酰胺(imidamide) [1107] (1) Synthesis of 3-methoxy-propane-carboximidamide (imidamide)

[1108] 室温下将11.7mL三甲基铝(23.4mmol,2.0M甲苯溶液)滴加至20mL(23.4mmol)含有1.26g氯化铵的甲苯。 [1108] A solution of trimethylaluminum 11.7mL (23.4mmol, 2.0M in toluene) was added dropwise to 20 mL (23.4 mmol) of toluene containing 1.26g of ammonium chloride. 搅拌1.5小时后,其中加入2g(23.4mmol)3-甲氧基丙腈,接着85℃下加热9小时。 After stirring for 1.5 hours, was added 2g (23.4mmol) 3- methoxypropionitrile, followed by heating at 85 ℃ 9 hours. 反应后,溶液冷却,然后向其中加入100mL含有200g硅胶的氯仿,接着过滤。 After the reaction, the solution was cooled, and 200g of silica gel containing 100mL of chloroform was added thereto, followed by filtration. 用100mL甲醇洗涤后,之后蒸馏,得到2.35g(23mmol)标题化合物,收率98%。 Washed with 100mL of methanol, after a distillation, to give 2.35g (23mmol) of the title compound in a yield of 98%.

[1109] NMR:1H-NMR(CD3OD)δ3.70(2H,t,J=7.0Hz),3.39(3H,s),2.73(2H,t,J=7.0Hz) [1109] NMR: 1H-NMR (CD3OD) δ3.70 (2H, t, J = 7.0Hz), 3.39 (3H, s), 2.73 (2H, t, J = 7.0Hz)

[1110] (2)合成2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1110] (2) Synthesis of 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1111] 将制备47获得的500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的173mg(1.69mmol)3-甲氧基丙烷酰亚胺酰胺添加至20mL吡啶,然后加热至90℃,接着搅拌约1.5小时。 [1111] A 500mg (1.69mmol) 3- oxo-47 obtained in Preparation 4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester, and the above step (1) 173mg (1.69mmol) obtained in 3 - methoxypropane 20mL of pyridine was added to the polyimide amide, and then heated to 90 ℃, followed by stirring for about 1.5 hours. 冷却至室温后,减压下蒸馏掉吡啶,残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到220mg标题化合物,总收率36%。 After cooling to room temperature, pyridine was distilled off under reduced pressure, the residue was purified by column chromatography (10:1 hexanes: ethyl acetate) to give the title compound 220mg, 36% overall yield.

[1112] 1H NMR(CDCl3)δ4.69(2H,s),3.90(2H,t,J=7.0Hz),3.70(2H,t,J=5.5Hz),3.35(3H,s),3.23(2H,t,J=7.0Hz),2.97(2H,br s),1.47(9H,s) [1112] 1H NMR (CDCl3) δ4.69 (2H, s), 3.90 (2H, t, J = 7.0Hz), 3.70 (2H, t, J = 5.5Hz), 3.35 (3H, s), 3.23 ( 2H, t, J = 7.0Hz), 2.97 (2H, br s), 1.47 (9H, s)

[1113] 质量(m/e)362(M+1) [1113] mass (m / e) 362 (M + 1)

[1114] (3)合成2-(2-甲氧基乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1114] (3) Synthesis of 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride salt

[1115] 利用上述步骤(2)获得的220mg(0.609mmol)2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得120mg标题化合物,收率75%。 [1115] obtained by the above step (2) of 220mg (0.609mmol) 2- (2- methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 120mg of the title compound in 75% yield.

[1116] 1H NMR(CD3OD)δ4.51(2H,s),3.93(2H,t,J=6.0Hz),3.63(2H,t,J=6.0Hz),3.2-3.4(7H,m) [1116] 1H NMR (CD3OD) δ4.51 (2H, s), 3.93 (2H, t, J = 6.0Hz), 3.63 (2H, t, J = 6.0Hz), 3.2-3.4 (7H, m)

[1117] 质量(m/e)262(M+1) [1117] mass (m / e) 262 (M + 1)

[1118] 制备90:合成2-(环丙基甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1118] Preparation 90: Synthesis of 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1119] (1)合成环丙基乙烷酰亚胺酰胺 [1119] (1) Synthesis of amide imide cyclopropyl oxide

[1120] 利用2.0g(25mmol)环丙基乙腈,以制备89(1)的相同方式,获得1.61g标题化合物,收率66%。 [1120] using 2.0g (25mmol) cyclopropyl acetonitrile to prepare a 89 (1) in the same manner to obtain the title compound 1.61g, yield 66%.

[1121] NMR:1H-NMR(CD3OD)δ2.39(2H,d,J=7.2Hz),1.09(1H,m),0.66(2H,m),0.35(2H,m) [1121] NMR: 1H-NMR (CD3OD) δ2.39 (2H, d, J = 7.2Hz), 1.09 (1H, m), 0.66 (2H, m), 0.35 (2H, m)

[1122] (2)合成2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1122] (2) Synthesis of 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate tert - butyl ester

[1123] 利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的166mg(1.69mmol)环丙基乙烷酰亚胺酰胺,以制备89(2)的相同方式,获得155mg标题化合物,收率26%。 166mg (1.69mmol butyl ester (the product of Preparation 47) and said step (1) obtained - [1123] using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert in the same manner) ethane cyclopropyl amide imide to prepare a 89 (2), to obtain 155mg of the title compound, yield 26%.

[1124] 1H NMR(CDCl3)δ4.70(2H,s),3.71(2H,t,J=6.0Hz),2.98(2H,brs),2.84(2H,d,J=7.5Hz),1.49(9H,s),1.25(1H,m),0.51(2H,m),0.29(2H,m) [1124] 1H NMR (CDCl3) δ4.70 (2H, s), 3.71 (2H, t, J = 6.0Hz), 2.98 (2H, brs), 2.84 (2H, d, J = 7.5Hz), 1.49 ( 9H, s), 1.25 (1H, m), 0.51 (2H, m), 0.29 (2H, m)

[1125] 质量(m/e)358(M+1) [1125] mass (m / e) 358 (M + 1)

[1126] (3)合成2-(环丙基甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1126] (3) Synthesis of 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1127] 利用上述步骤(2)获得的155mg(0.43mmol)2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得85mg标题化合物,收率76%。 [1127] With the above steps (2) obtained 155mg (0.43mmol) 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 85mg of the title compound, yield 76%.

[1128] 1H NMR(CD3OD)δ4.33(2H,s),3.37(2H,t,J=6.5Hz),2.63(2H,d,J=6.0Hz),1.0(1H,m),0.30(2H,m),0.1(2H,m) [1128] 1H NMR (CD3OD) δ4.33 (2H, s), 3.37 (2H, t, J = 6.5Hz), 2.63 (2H, d, J = 6.0Hz), 1.0 (1H, m), 0.30 ( 2H, m), 0.1 (2H, m)

[1129] 质量(m/e)258(M+1) [1129] mass (m / e) 258 (M + 1)

[1130] 制备91:合成2-吡啶-4-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1130] Preparation 91: Synthesis of 2-pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1131] (1)合成吡啶-4-脒(carboximidamide) [1131] (1) Synthesis of pyridin-4-amidine (-carboximidamide)

[1132] 利用2.0g(19.2mmol)氰基吡啶(isonicotinonitrile),以制备89(1)的相同方式,获得1.06g标题化合物,收率45%。 [1132] using 2.0g (19.2mmol) cyanopyridine (isonicotinonitrile), prepared in the same manner as 89 (1), to obtain 1.06g of the title compound in 45% yield.

[1133] NMR:1H-NMR(CD3OD)δ8.86(2H,m),7.79(2H,m) [1133] NMR: 1H-NMR (CD3OD) δ8.86 (2H, m), 7.79 (2H, m)

[1134] (2)合成2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1134] (2) Synthesis of 2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1135] 利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的210mg(1.69mmol)吡啶-4-脒,以制备89(2)的相同方式,获得240mg标题化合物,收率37%。 [1135] using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 210mg-butyl ester (the product of Preparation 47) and said step (1) obtained in (1.69 mmol ) pyridine-4-carboxamidine, 89 was prepared in the same manner as (2), to obtain 240mg of the title compound in 37% yield.

[1136] 1H NMR(CDCl3)δ8.78(2H,d,J=5.5Hz),8.30(2H,d,J=5.5Hz),4.81(2H,s),3.76(2H,t,J=6.0Hz),3.07(2H,br s),1.51(9H,s) [1136] 1H NMR (CDCl3) δ8.78 (2H, d, J = 5.5Hz), 8.30 (2H, d, J = 5.5Hz), 4.81 (2H, s), 3.76 (2H, t, J = 6.0 hz), 3.07 (2H, br s), 1.51 (9H, s)

[1137] 质量(m/e)381(M+1) [1137] mass (m / e) 381 (M + 1)

[1138] (3)合成2-吡啶-4-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1138] (3) Synthesis of 2-pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1139] 利用上述步骤(2)获得的240mg(0.63mmol)2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得160mg标题化合物,收率90%。 [1139] obtained by the above step (2) 240mg (0.63mmol) 2- pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 160mg of the title compound in 90% yield.

[1140] 1H NMR(CD3OD)δ9.07(2H,d,J=6.0Hz),9.02(2H,d,J=6.0Hz),4.71(2H,s),3.70(2H,brt,J=6.0Hz),3.43(2H,br s) [1140] 1H NMR (CD3OD) δ9.07 (2H, d, J = 6.0Hz), 9.02 (2H, d, J = 6.0Hz), 4.71 (2H, s), 3.70 (2H, brt, J = 6.0 hz), 3.43 (2H, br s)

[1141] 质量(m/e)281(M+1) [1141] mass (m / e) 281 (M + 1)

[1142] 制备92:合成2-(4-氟苄基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1142] Preparation 92: Synthesis of 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1143] (1)合成2-(4-氟苯基)乙烷酰亚胺酰胺 [1143] (1) Synthesis of 2- (4-fluorophenyl) ethane imide-amide

[1144] 利用2.0g(14.8mmol)(4-氟苯基)乙腈,以制备89(1)的相同方式,获得2.0g标题化合物,收率89%。 [1144] using 2.0g (14.8mmol) (4- fluorophenyl) acetonitrile, to prepare a 89 (1) in the same manner to obtain 2.0g of the title compound in 89% yield.

[1145] NMR:1H-NMR(CD3OD)δ7.50(2H,m),7.15(2H,m),3.90(2H,s) [1145] NMR: 1H-NMR (CD3OD) δ7.50 (2H, m), 7.15 (2H, m), 3.90 (2H, s)

[1146] (2)合成2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1146] (2) Synthesis of 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate tert - butyl ester

[1147] 利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的258mg(1.69mmol)2-(4-氟苯基)乙烷酰亚胺酰胺,以制备89(2)的相同方式,获得250mg标题化合物,收率36%。 [1147] using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 258mg-butyl ester (the product of Preparation 47) and said step (1) obtained in (1.69 mmol ) in the same manner 2- (4-fluorophenyl) ethane polyimide amide, to prepare a 89 (2), to obtain 250mg of the title compound in 36% yield.

[1148] 1H NMR(CDCl3)δ7.37(2H,m),6.95(2H,t,J=8.0Hz),4.67(2H,s),4.24(2H,s),3.69(2H,t,J=6.0Hz),2.96(2H,br s),1.49(9H,s) [1148] 1H NMR (CDCl3) δ7.37 (2H, m), 6.95 (2H, t, J = 8.0Hz), 4.67 (2H, s), 4.24 (2H, s), 3.69 (2H, t, J = 6.0Hz), 2.96 (2H, br s), 1.49 (9H, s)

[1149] 质量(m/e)412(M+1) [1149] mass (m / e) 412 (M + 1)

[1150] (3)合成2-(4-氟苄基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1150] (3) Synthesis of 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1151] 利用上述步骤(2)获得的250mg(0.61mmol)2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得77mg标题化合物,收率41%。 [1151] obtained by the above step (2) 250mg (0.61mmol) 2- (4- fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 77mg of the title compound in 41% yield.

[1152] 1H NMR(CD3OD)δ7.35(2H,m),6.99(2H,t,J=9.0Hz),4.45(2H,s),4.27(2H,s),3.57(2H,t,J=6.5Hz),3.23(2H,t,J=6.5Hz) [1152] 1H NMR (CD3OD) δ7.35 (2H, m), 6.99 (2H, t, J = 9.0Hz), 4.45 (2H, s), 4.27 (2H, s), 3.57 (2H, t, J = 6.5Hz), 3.23 (2H, t, J = 6.5Hz)

[1153] 质量(m/e)312(M+1) [1153] mass (m / e) 312 (M + 1)

[1154] 制备93:合成2-(3-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1154] Preparation 93: Synthesis of 2- (3-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1155] (1)合成噻吩-3-脒 [1155] (1) Synthesis of thiophen-3-carboxamidine

[1156] 利用1.64g(15mmol)噻吩-3-腈,以制备89(1)的相同方式,获得1.81g标题化合物,收率95%。 [1156] using 1.64g (15mmol) thiophene-3-carbonitrile, prepared in 89 (1) in the same manner to obtain the title compound 1.81g, 95% yield.

[1157] NMR:1H-NMR(CD3OD)δ8.41(1H,m),7.69(1H,m),7.59(1H,m) [1157] NMR: 1H-NMR (CD3OD) δ8.41 (1H, m), 7.69 (1H, m), 7.59 (1H, m)

[1158] (2)合成2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1158] (2) Synthesis of 2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1159] 利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的214mg(1.69mmol)噻吩-3-脒,以制备89(2)的相同方式,获得228mg标题化合物,收率35%。 [1159] using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 214mg-butyl ester (the product of Preparation 47) and said step (1) obtained in (1.69 mmol ) thiophene-3-carboxamidine, prepared in 89 (2) in the same manner, to obtain 228mg of the title compound in 35% yield.

[1160] 1H NMR(CDCl3)δ8.34(1H,m),7.90(1H,m),7.38(1H,m),4.74(2H,s),3.74(2H,t,J=6.0Hz),3.00(2H,br s),1.51(9H,s) [1160] 1H NMR (CDCl3) δ8.34 (1H, m), 7.90 (1H, m), 7.38 (1H, m), 4.74 (2H, s), 3.74 (2H, t, J = 6.0Hz), 3.00 (2H, br s), 1.51 (9H, s)

[1161] 质量(m/e)386(M+1) [1161] mass (m / e) 386 (M + 1)

[1162] (3)合成2-(3-噻吩基)-4-(三氟甲基)-5678-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1162] (3) Synthesis of 2- (3-thienyl) -4- (trifluoromethyl) -5678- tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1163] 利用上述步骤(2)获得的228mg(0.59mmo1)2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得168mg标题化合物,收率61%。 [1163] obtained by the above step (2) 228mg (0.59mmo1) 2- (3- thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 168mg of the title compound in 61% yield.

[1164] 1H NMR(CD3OD)δ8.42(1H,m),7.86(1H,m),7.53(1H,m),4.53(2H,s),3.62(2H,t,J=6.5Hz),3.30(2H,m) [1164] 1H NMR (CD3OD) δ8.42 (1H, m), 7.86 (1H, m), 7.53 (1H, m), 4.53 (2H, s), 3.62 (2H, t, J = 6.5Hz), 3.30 (2H, m)

[1165] 质量(m/e)286(M+1) [1165] mass (m / e) 286 (M + 1)

[1166] 制备94:合成2-(2-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1166] Preparation 94: Synthesis of 2- (2-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1167] (1)合成噻吩-2-脒 [1167] (1) Synthesis of thiophene-2-carboxamidine

[1168] 利用1.64g(15mmol)噻吩-2-腈,以制备89(1)的相同方式,获得1.8g标题化合物,收率95%。 [1168] using 1.64g (15mmol) thiophene-2-carbonitrile, prepared in 89 (1) in the same manner to obtain the title compound 1.8g, 95% yield.

[1169] NMR:1H-NMR(CD3OD)δ7.94(1H,m),7.89(1H,m),7.24(1H,m) [1169] NMR: 1H-NMR (CD3OD) δ7.94 (1H, m), 7.89 (1H, m), 7.24 (1H, m)

[1170] (2)合成2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1170] (2) Synthesis of 2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1171] 利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的146mg(1.69mmol)噻吩-2-脒,以制备89(2)的相同方式,获得144mg标题化合物,收率25%。 146mg (1.69mmol butyl ester (the product of Preparation 47) and said step (1) obtained - [1171] using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert ) thiophene-2-carboxamidine, prepared in 89 (2) in the same manner to obtain the title compound 144mg, 25% yield.

[1172] 1H NMR(CDCl3)δ8.04(1H,d,J=4.0Hz),7.50(1H,d,J=5.0Hz),7.14(1H,m),4.72(2H,s),3.72(2H,t,J=5.5Hz),2.99(2H,br s),1.54(9H,s) [1172] 1H NMR (CDCl3) δ8.04 (1H, d, J = 4.0Hz), 7.50 (1H, d, J = 5.0Hz), 7.14 (1H, m), 4.72 (2H, s), 3.72 ( 2H, t, J = 5.5Hz), 2.99 (2H, br s), 1.54 (9H, s)

[1173] 质量(m/e)386(M+1) [1173] mass (m / e) 386 (M + 1)

[1174] (3)合成2-(2-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1174] (3) Synthesis of 2- (2-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1175] 利用上述步骤(2)获得的144mg(0.42mmol)2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得72mg标题化合物,收率61%。 [1175] With the above steps (2) obtained 144mg (0.42mmol) 2- (2- thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 72mg of the title compound in 61% yield.

[1176] 1H NMR(CD3OD)δ8.09(1H,m),7.72(1H,m),7.23(1H,m),4.55(2H,s),3.64(2H,t,J=6.5Hz),3.30(2H,m) [1176] 1H NMR (CD3OD) δ8.09 (1H, m), 7.72 (1H, m), 7.23 (1H, m), 4.55 (2H, s), 3.64 (2H, t, J = 6.5Hz), 3.30 (2H, m)

[1177] 质量(m/e)286(M+1) [1177] mass (m / e) 286 (M + 1)

[1178] 制备95:合成2-(2-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1178] Preparation 95: Synthesis of 2- (2-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1179] (1)合成呋喃-2-脒 [1179] (1) Synthesis of furan-2-carboxamidine

[1180] 利用2.77g(30mmol)2-糠腈,以制备89(1)的相同方式,获得2.1g标题化合物,收率64%。 [1180] using 2.77g (30mmol) 2- furonitrile, prepared in the same manner as 89 (1), to obtain the title compound 2.1g, 64% yield.

[1181] NMR:1H-NMR(CD3OD)δ7.94(1H,s),7.58(1H,d,J=3.6Hz),6.78(1H,m) [1181] NMR: 1H-NMR (CD3OD) δ7.94 (1H, s), 7.58 (1H, d, J = 3.6Hz), 6.78 (1H, m)

[1182] (2)合成2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔丁酯 [1182] (2) Synthesis of 2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate butyl

[1183] 利用3g(10.2mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的1.12g(10.2mmol)呋喃-2-脒,以制备89(2)的相同方式,获得2.55g标题化合物,收率68%。 [1183] using 3g (10.2mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester, and the above step (the product of Preparation 47) (1) obtained in 1.12g (10.2 mmol) furan-2-carboxamidine, 89 was prepared in the same manner as (2) to give the title compound 2.55g, 68% yield.

[1184] 1H NMR(CDCl3)δ7.65(1H,s),7.39(1H,d,J=3.0Hz),6.58(1H,m),4.78(2H,s),3.73(2H,t,J=5.5Hz),3.0(2H,br s),1.49(9H,s) [1184] 1H NMR (CDCl3) δ7.65 (1H, s), 7.39 (1H, d, J = 3.0Hz), 6.58 (1H, m), 4.78 (2H, s), 3.73 (2H, t, J = 5.5Hz), 3.0 (2H, br s), 1.49 (9H, s)

[1185] 质量(m/e)370(M+1) [1185] mass (m / e) 370 (M + 1)

[1186] (3)合成2-(2-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1186] (3) Synthesis of 2- (2-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1187] 利用上述步骤(2)获得的2.55g(6.9mmol)2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得1.42g标题化合物,收率67%。 [1187] obtained by the above step (2) of 2.55g (6.9mmol) 2- (2- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester, prepared in the same manner as 58 (3), to obtain 1.42g of the title compound in 67% yield.

[1188] 1H NMR(CD3OD)δ7.58(1H,s),7.43(1H,d,J=3.7Hz),6.67(1H,m),4.51(2H,s),3.61(2H,t,J=6.5Hz),3.26(2H,t,J=6.5Hz) [1188] 1H NMR (CD3OD) δ7.58 (1H, s), 7.43 (1H, d, J = 3.7Hz), 6.67 (1H, m), 4.51 (2H, s), 3.61 (2H, t, J = 6.5Hz), 3.26 (2H, t, J = 6.5Hz)

[1189] 质量(m/e)270(M+1) [1189] mass (m / e) 270 (M + 1)

[1190] 制备96:合成2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1190] Preparation 96: Synthesis of 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1191] (1)合成呋喃-3-脒 [1191] (1) Synthesis of furan-3-carboxamidine

[1192] 利用1.4g(15mmol)3-糠腈,以制备89(1)的相同方式,获得1.56g标题化合物,收率94%。 The same manner as [1192] using 1.4g (15mmol) 3- furonitrile to prepare a 89 (1), to obtain 1.56g of the title compound in 94% yield.

[1193] NMR:1H-NMR(CD3OD)δ8.4(1H,s),7.76(1H,m),6.96(1H,m) [1193] NMR: 1H-NMR (CD3OD) δ8.4 (1H, s), 7.76 (1H, m), 6.96 (1H, m)

[1194] (2)合成2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1194] (2) Synthesis of 2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1195] 利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的186mg(1.69mmol)呋喃-3-脒,以制备89(2)的相同方式,获得170mg标题化合物,收率27%。 186mg (1.69mmol butyl ester (the product of Preparation 47) and said step (1) obtained - [1195] using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert ) furan-3-carboxamidine, prepared in 89 (2) in the same manner, to obtain 170mg of the title compound in 27% yield.

[1196] 1H NMR(CDCl3)δ8.26(1H,s),7.49(1H,s),7.06(1H,s),4.70(2H,s),3.72(2H,t,J=5.5Hz),3.0(2H,br s),1.54(9H,s) [1196] 1H NMR (CDCl3) δ8.26 (1H, s), 7.49 (1H, s), 7.06 (1H, s), 4.70 (2H, s), 3.72 (2H, t, J = 5.5Hz), 3.0 (2H, br s), 1.54 (9H, s)

[1197] 质量(m/e)370(M+1) [1197] mass (m / e) 370 (M + 1)

[1198] (3)合成2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1198] (3) Synthesis of 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1199] 利用上述步骤(2)获得的170mg(0.46mmol)2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得86mg标题化合物,收率69%。 [1199] With the above steps (2) obtained 170mg (0.46mmol) 2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 86mg of the title compound in 69% yield.

[1200] 1H NMR(CD3OD)δ8.39(1H,s),7.67(1H,m),7.09(1H,m),4.54(2H,s),3.65(2H,t,J=6.0Hz),3.29(2H,t,J=6.0Hz) [1200] 1H NMR (CD3OD) δ8.39 (1H, s), 7.67 (1H, m), 7.09 (1H, m), 4.54 (2H, s), 3.65 (2H, t, J = 6.0Hz), 3.29 (2H, t, J = 6.0Hz)

[1201] 质量(m/e)270(M+1) [1201] mass (m / e) 270 (M + 1)

[1202] 制备97:合成2-吡啶-3-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1202] Preparation 97: Synthesis of 2-pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1203] (1)合成2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1203] (1) Synthesis of 2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1204] 利用700mg(2.37mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的370mg(2.37mmol)吡啶-3-脒,以制备89(2)的相同方式,获得640mg标题化合物,收率71%。 [1204] using 700mg (2.37mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester (the product of Preparation 47) and said step (1) obtained 370mg (2.37mmol ) pyridine-3-carboxamidine, prepared in 89 (2) in the same manner to obtain the title compound 640mg, 71% yield.

[1205] 1H NMR(CDCl3)δ9.65(1H,s),8.73(2H,m),7.43(1H,m),4.80(2H,s),3.76(2H,t,J=5.5Hz),3.05(2H,br s),1.51(9H,s) [1205] 1H NMR (CDCl3) δ9.65 (1H, s), 8.73 (2H, m), 7.43 (1H, m), 4.80 (2H, s), 3.76 (2H, t, J = 5.5Hz), 3.05 (2H, br s), 1.51 (9H, s)

[1206] 质量(m/e)381(M+1) [1206] mass (m / e) 381 (M + 1)

[1207] (2)合成2-吡啶-3-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1207] (2) Synthesis of 2-pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1208] 利用上述步骤(2)获得的640mg(1.68mmol)2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58(3)的相同方式,获得500mg标题化合物,收率94%。 [1208] With the above steps (2) obtained 640mg (1.68mmol) 2- pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - carboxylic acid tert - butyl ester, 58 was prepared in the same manner as (3), to obtain 500mg of the title compound in 94% yield.

[1209] 1H NMR(CD3OD)δ9.72(1H,s),9.49(1H,m),9.00(1H,br s),8.23(1H,m),4.67(2H,s),3.66(2H,t,J=5.5Hz),3.39(2H,br s) [1209] 1H NMR (CD3OD) δ9.72 (1H, s), 9.49 (1H, m), 9.00 (1H, br s), 8.23 ​​(1H, m), 4.67 (2H, s), 3.66 (2H, t, J = 5.5Hz), 3.39 (2H, br s)

[1210] 质量(m/e)281(M+1) [1210] mass (m / e) 281 (M + 1)

[1211] 制备98:合成2-(1H-吡咯-2-基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1211] Preparation 98: Synthesis of 2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride salt

[1212] (1)合成1H-吡咯-2-脒 [1212] (1) Synthesis of 1H- pyrrole-2-carboxamidine

[1213] 利用1.38g(15mmol)1H-吡咯-2-腈,以制备89-(1)的相同方式,获得1.09g标题化合物,收率67%。 [1213] using 1.38g (15mmol) 1H- pyrrole-2-carbonitrile, prepared 89- (1) in the same manner to obtain the title compound 1.09g, 67% yield.

[1214] NMR:1H-NMR(CD3OD)δ7.12(2H,m),6.31(1H,t,J=3.3Hz) [1214] NMR: 1H-NMR (CD3OD) δ7.12 (2H, m), 6.31 (1H, t, J = 3.3Hz)

[1215] (2)合成2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1215] (2) Synthesis of 2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1216] 利用800mg(2.7mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯(制备47的产物)和上述步骤(1)获得的300mg(2.7mmol)1H-吡咯-2-脒,以制备89(2)的相同方式,获得185mg标题化合物,收率19%。 [1216] using 800mg (2.7mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 300mg-butyl ester (the product of Preparation 47) and said step (1) obtained in (2.7 mmol ) lH-pyrrole-2-carboxamidine, 89 was prepared in the same manner as (2) to give the title compound 185mg, 19% yield.

[1217] 1H NMR(CDCl3)δ7.14(1H,m),6.98(1H,m),6.34(1H,m),7.18(1H,m),4.67(2H,s),3.71(2H,t,J=5.5Hz),2.95(2H,br s),1.49(9H,s) [1217] 1H NMR (CDCl3) δ7.14 (1H, m), 6.98 (1H, m), 6.34 (1H, m), 7.18 (1H, m), 4.67 (2H, s), 3.71 (2H, t , J = 5.5Hz), 2.95 (2H, br s), 1.49 (9H, s)

[1218] 质量(m/e)369(M+1) [1218] mass (m / e) 369 (M + 1)

[1219] (3)合成2-(1H-吡咯-2-基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1219] (3) Synthesis of 2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride salt

[1220] 利用上述步骤(2)获得的185mg(0.50mmol)2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备58-(3)的相同方式,获得48mg标题化合物,收率36%。 [1220] With the above steps (2) obtained 185mg (0.50mmol) 2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester, was prepared in the same manner as 58- (3), to obtain 48mg of the title compound in 36% yield.

[1221] 1H NMR(CD3OD)δ11.25(1H,m),7.08(1H,m),7.00(1H,m),6.26(1H,m),4.45(2H,s),3.59(2H,t,J=5.5Hz),3.20(2H,t,J=5.5Hz) [1221] 1H NMR (CD3OD) δ11.25 (1H, m), 7.08 (1H, m), 7.00 (1H, m), 6.26 (1H, m), 4.45 (2H, s), 3.59 (2H, t , J = 5.5Hz), 3.20 (2H, t, J = 5.5Hz)

[1222] 质量(m/e)269(M+1) [1222] mass (m / e) 269 (M + 1)

[1223] 制备99:合成[(S)-3-[2-(2-甲氧基乙基)-4-三氟甲基]-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氢代丙基]氨基甲酸叔-丁酯 [1223] Preparation 99: Synthesis of [(S) -3- [2- (2- methoxyethyl) -4-trifluoromethyl] -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl hydrogen] carbamic acid tert - butyl ester

[1224] 除了利用制备51获得的44.0mg(0.139mmole)(3S)-3-叔-丁氧基羰基氨基-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备89获得的37.5mg(0.126mmole)2-(2-甲氧基乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得61mg标题化合物,收率79%。 [1224] Preparation 51 except using the obtained 44.0mg (0.139mmole) (3S) -3- tert - butoxycarbonylamino-amino -4 - [(5R) -5- methyl-2-oxo-piperidine-1 yl] butanoic acid obtained in 89 preparation and 37.5mg (0.126mmole) 2- (2- methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3 addition, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 61mg of the title compound in 79% yield.

[1225] 1H NMR(CDCl3)δ5.89-5.87(1H,m),4.90-4.79(1H,m),4.78-4.67(1H,m),4.20-4.15(1H,m),3.92-3.82(2H,m),3.78-3.75(1H,m),3.64-3.47(4H,m),3.39-3.36(4H,m),3.26-3.23(2H,m),3.11-2.99(3H,m),2.87-2.80(1H,m),2.55-2.27(3H,m),1.97-1.93(1H,m),1.84-1.81(1H,m),1.42-1.41(9H,m),1.00(3H,d,J=5.6Hz) [1225] 1H NMR (CDCl3) δ5.89-5.87 (1H, m), 4.90-4.79 (1H, m), 4.78-4.67 (1H, m), 4.20-4.15 (1H, m), 3.92-3.82 ( 2H, m), 3.78-3.75 (1H, m), 3.64-3.47 (4H, m), 3.39-3.36 (4H, m), 3.26-3.23 (2H, m), 3.11-2.99 (3H, m), 2.87-2.80 (1H, m), 2.55-2.27 (3H, m), 1.97-1.93 (1H, m), 1.84-1.81 (1H, m), 1.42-1.41 (9H, m), 1.00 (3H, d , J = 5.6Hz)

[1226] 质量(m/e)558(M+1) [1226] mass (m / e) 558 (M + 1)

[1227] 实施例52:合成(5R)-1-{(2S)-2-氨基-4-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1227] Example 52: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8 - dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1228] [1228]

[1229] 利用制备99获得的61mg(0.109mmole)[(1S)-3-[2-(2-甲氧基乙基)-4-三氟甲基]-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯,以实施例22的相同方式,获得51.9mg标题化合物,收率96%。 [1229] using 61mg (0.109mmole) [(1S) -3- [2- (2- methoxyethyl) -4-trifluoromethyl] -5,8-dihydropyridine obtained in Preparation 99 and [ 3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl ] carbamic acid tert - butyl ester, in the same manner as in Example 22 to give the title compound 51.9mg, yield 96%.

[1230] 1H NMR(CD3OD)δ4.92-4.80(2H,m),3.94-3.83(4H,m),3.67(1H,brs),3.54-3.53(2H,m),3.42-3.34(4H,m),3.24-3.21(2H,m),3.12-3.01(3H,m),2.82-2.77(1H,m),2.70-2.60(1H,m),2.47-2.32(2H,m),2.05-2.00(1H,m),1.88-1.85(1H,m),1.59-1.48(1H,m),1.04(3H,d,J=6.4Hz) [1230] 1H NMR (CD3OD) δ4.92-4.80 (2H, m), 3.94-3.83 (4H, m), 3.67 (1H, brs), 3.54-3.53 (2H, m), 3.42-3.34 (4H, m), 3.24-3.21 (2H, m), 3.12-3.01 (3H, m), 2.82-2.77 (1H, m), 2.70-2.60 (1H, m), 2.47-2.32 (2H, m), 2.05- 2.00 (1H, m), 1.88-1.85 (1H, m), 1.59-1.48 (1H, m), 1.04 (3H, d, J = 6.4Hz)

[1231] 质量(m/e)458(M+1) [1231] mass (m / e) 458 (M + 1)

[1232] 制备100:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1232] Preparation 100: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (2-methoxyethyl yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1233] 利用制备57获得的47.0mg(0.139mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备89获得的37.5mg(0.126mmole)2-(2-甲氧基乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得47mg标题化合物,收率58%。 [1233] 57 was prepared using the obtained 47.0mg (0.139mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and prepared 37.5mg (0.126mmole) 89 to obtain 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [ 3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 47mg, 58% yield.

[1234] 1H NMR(CDCl3)δ5.79-5.78(1H,m),4.90-4.79(1H,m),4.76-4.65(1H,m),4.25-4.20(1H,m),3.92-3.86(3H,m),3.80-3.68(3H,m),3.63-3.53(2H,m),3.36(3H,s),3.26-3.23(2H,m),3.01-2.99(2H,m),2.85-2.78(1H,m),2.61-2.50(3H,m),2.32-2.20(2H,m),1.42-1.41(9H,m) [1234] 1H NMR (CDCl3) δ5.79-5.78 (1H, m), 4.90-4.79 (1H, m), 4.76-4.65 (1H, m), 4.25-4.20 (1H, m), 3.92-3.86 ( 3H, m), 3.80-3.68 (3H, m), 3.63-3.53 (2H, m), 3.36 (3H, s), 3.26-3.23 (2H, m), 3.01-2.99 (2H, m), 2.85- 2.78 (1H, m), 2.61-2.50 (3H, m), 2.32-2.20 (2H, m), 1.42-1.41 (9H, m)

[1235] 质量(m/e)580(M+1) [1235] mass (m / e) 580 (M + 1)

[1236] 实施例53:合成1-{(2S)-2-氨基-4-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1236] Example 53: Synthesis of 1 - {(2S) -2- amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1237] [1237]

[1238] 利用制备100获得的47mg(0.081mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得25.4mg标题化合物,收率61%。 47mg [1238] 100 was prepared using the obtained (0.081mmole) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- ( 2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester, in the same manner as Example 22 to give 25.4mg of the title compound in 61% yield.

[1239] 1H NMR(CD3OD)δ4.86-4.80(2H,m),3.94-3.90(3H,m),3.89-3.75(3H,m),3.57-3.45(3H,m),3.34-3.32(3H,m),3.24-3.21(2H,m),3.11-3.01(2H,m),2.73-2.51(4H,m),2.41-2.30(2H,m) [1239] 1H NMR (CD3OD) δ4.86-4.80 (2H, m), 3.94-3.90 (3H, m), 3.89-3.75 (3H, m), 3.57-3.45 (3H, m), 3.34-3.32 ( 3H, m), 3.24-3.21 (2H, m), 3.11-3.01 (2H, m), 2.73-2.51 (4H, m), 2.41-2.30 (2H, m)

[1240] 质量(m/e)480(M+1) [1240] mass (m / e) 480 (M + 1)

[1241] 制备101:合成{(1S)-3-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯 [1241] Preparation 101: Synthesis of {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester

[1242] 利用制备51获得的50.0mg(0.159mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备90获得的43.0mg(0.145mmole)2-(环丙基甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得66mg标题化合物,收率75%。 [1242] 51 was prepared using the obtained 50.0mg (0.159mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 43.0mg (0.145mmole) 90 preparation of 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [ 3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 66mg of the title compound in 75% yield.

[1243] 1H NMR(CDCl3)δ5.88(1H,brs),4.90-4.80(1H,m),4.78-4.66(1H,m),4.20-4.18(1H,m),3.93-3.85(1H,m),3.79-3.76(1H,m),3.65-3.47(2H,m),3.43-3.33(1H,m),3.11-2.99(3H,m),2.86-2.81(3H,m),2.56-2.27(3H,m),2.02-1.93(1H,m),1.84-1.81(1H,m),1.42-1.41(9H,m),1.30-1.17(2H,m),1.00(3H,d,J=6.4Hz),0.55-0.49(2H,m),0.34-0.28(2H,m) [1243] 1H NMR (CDCl3) δ5.88 (1H, brs), 4.90-4.80 (1H, m), 4.78-4.66 (1H, m), 4.20-4.18 (1H, m), 3.93-3.85 (1H, m), 3.79-3.76 (1H, m), 3.65-3.47 (2H, m), 3.43-3.33 (1H, m), 3.11-2.99 (3H, m), 2.86-2.81 (3H, m), 2.56- 2.27 (3H, m), 2.02-1.93 (1H, m), 1.84-1.81 (1H, m), 1.42-1.41 (9H, m), 1.30-1.17 (2H, m), 1.00 (3H, d, J = 6.4Hz), 0.55-0.49 (2H, m), 0.34-0.28 (2H, m)

[1244] 质量554(m/e)(M+1) [1244] mass 554 (m / e) (M + 1)

[1245] 实施例54:合成(5R)-1-{(2S)-2-氨基-4-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1245] Example 54: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1246] [1246]

[1247] 利用制备101获得的66mg(0.119mmole){(1S)-3-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得47.9mg标题化合物,收率82%。 [1247] using 66mg (0.119mmole) {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyridine obtained and prepared 101 [3 , 4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester, in the same manner as in Example 22 to obtain 47.9mg of the title compound in 82% yield.

[1248] 1H NMR(CD3OD)δ4.68-4.56(2H,m),3.70-3.58(2H,m),3.40-3.37(1H,m),3.31-3.21(2H,m),3.17-3.12(1H,m),2.87-2.77(3H,m),2.62-2.60(2H,m),2.53-2.48(1H,m),2.41-2.35(1H,m),2.20-2.11(2H,m),1.79-1.76(1H,m),1.63-1.59(1H,m),1.34-1.23(1H,m),1.06-0.97(1H,m),0.80(3H,d,J=6.4Hz),0.31-0.23(2H,m),0.11-0.04(2H,m), [1248] 1H NMR (CD3OD) δ4.68-4.56 (2H, m), 3.70-3.58 (2H, m), 3.40-3.37 (1H, m), 3.31-3.21 (2H, m), 3.17-3.12 ( 1H, m), 2.87-2.77 (3H, m), 2.62-2.60 (2H, m), 2.53-2.48 (1H, m), 2.41-2.35 (1H, m), 2.20-2.11 (2H, m), 1.79-1.76 (1H, m), 1.63-1.59 (1H, m), 1.34-1.23 (1H, m), 1.06-0.97 (1H, m), 0.80 (3H, d, J = 6.4Hz), 0.31- 0.23 (2H, m), 0.11-0.04 (2H, m),

[1249] 质量(m/e)454(M+1) [1249] mass (m / e) 454 (M + 1)

[1250] 制备102:合成{(1S)-3-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1250] Preparation 102: Synthesis of {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1251] 利用制备57获得的53.5mg(0.159mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备90获得的43.0mg(0.145mmole)2-(环丙基甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得66mg标题化合物,收率75%。 [1251] 57 was prepared using the obtained 53.5mg (0.159mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and obtained in preparation 90 43.0mg (0.145mmole) 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 66mg of the title compound in 75% yield.

[1252] 1H NMR(CDCl3)δ5.77(1H,brs),4.87-4.80(1H,m),4.73-4.62(1H,m),4.19(1H,brs),3.89-3.86(1H,m),3.78-3.68(3H,m),3.61-3.55(2H,m),3.05-2.92(2H,m),2.84-2.79(3H,m),2.59-2.47(3H,m),2.29-2.15(2H,m),1.40-1.39(9H,m),1.24-1.23(1H,m),0.53-0.49(2H,m),0.28-0.27(2H,m) [1252] 1H NMR (CDCl3) δ5.77 (1H, brs), 4.87-4.80 (1H, m), 4.73-4.62 (1H, m), 4.19 (1H, brs), 3.89-3.86 (1H, m) , 3.78-3.68 (3H, m), 3.61-3.55 (2H, m), 3.05-2.92 (2H, m), 2.84-2.79 (3H, m), 2.59-2.47 (3H, m), 2.29-2.15 ( 2H, m), 1.40-1.39 (9H, m), 1.24-1.23 (1H, m), 0.53-0.49 (2H, m), 0.28-0.27 (2H, m)

[1253] 质量(m/e)576(M+1) [1253] mass (m / e) 576 (M + 1)

[1254] 实施例55:合成1-{(2S)-2-氨基-4-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1254] Example 55: Synthesis of 1 - {(2S) -2- amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1255] [1255]

[1256] 利用制备102获得的61mg(0.106mmole){(1S)-3-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得35.9mg标题化合物,收率66%。 [1256] using 61mg (0.106mmole) {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyridine obtained and prepared 102 [3 , 4-d] pyrimidin -7 (6H) - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamate tert - butyl ester, in the same manner as Example 22 to give the title compound 35.9mg, yield 66%.

[1257] 1H NMR(CD3OD)δ4.67-4.55(2H,m),3.62-3.54(4H,m),3.30-3.23(3H,m),2.87-2.77(2H,m),2.62-2.60(2H,m),2.48-2.27(4H,m),2.17-2.06(2H,m),1.03-0.98(1H,m),0.31-0.26(2H,m),0.07-0.04(2H,m) [1257] 1H NMR (CD3OD) δ4.67-4.55 (2H, m), 3.62-3.54 (4H, m), 3.30-3.23 (3H, m), 2.87-2.77 (2H, m), 2.62-2.60 ( 2H, m), 2.48-2.27 (4H, m), 2.17-2.06 (2H, m), 1.03-0.98 (1H, m), 0.31-0.26 (2H, m), 0.07-0.04 (2H, m)

[1258] 质量(m/e)476(M+1) [1258] mass (m / e) 476 (M + 1)

[1259] 制备103:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1259] Preparation 103: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1260] 利用制备51获得的44.0mg(0.140mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备91获得的45.0mg(0.127mmole)2-吡啶-4-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得50mg标题化合物,收率62%。 [1260] 44.0mg 51 prepared using the obtained (0.140mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid obtained in preparation 91 and 45.0mg (0.127mmole) 2- pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 50mg, 62% yield.

[1261] 1H NMR(CDCl3)δ8.80-8.79(2H,m),8.31(2H,m),5.89(1H,brs),5.03-4.79(2H,m),4.20(1H,brs),3.94(1H,brs),3.70(1H,brs),3.60-3.46(2H,m),3.39-3.36(1H,m),3.17-3.04(3H,m),2.87(1H,brs),2.56-2.51(1H,m),2.44-2.31(2H,m),1.96(1H,brs),1.82(2H,brs),1.43-1.41(9H,m),1.00(3H,d,J=6.4Hz) [1261] 1H NMR (CDCl3) δ8.80-8.79 (2H, m), 8.31 (2H, m), 5.89 (1H, brs), 5.03-4.79 (2H, m), 4.20 (1H, brs), 3.94 (1H, brs), 3.70 (1H, brs), 3.60-3.46 (2H, m), 3.39-3.36 (1H, m), 3.17-3.04 (3H, m), 2.87 (1H, brs), 2.56-2.51 (1H, m), 2.44-2.31 (2H, m), 1.96 (1H, brs), 1.82 (2H, brs), 1.43-1.41 (9H, m), 1.00 (3H, d, J = 6.4Hz)

[1262] 质量577(m/e)(M+1) [1262] mass 577 (m / e) (M + 1)

[1263] 实施例56:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [1263] Example 56: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5, 8- dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[1264] [1264]

[1265] 利用制备103获得的50mg(0.087mmole){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得33.6mg标题化合物,收率81%。 [1265] using 50mg (0.087mmole) {(1S) -1 obtained in Preparation 103 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo -3- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl ester, in the same manner as Example 22 to give the title compound 33.6mg, 81% yield.

[1266] 1H NMR(CD3OD)δ8.77-8.75(2H,m),8.44-8.42(2H,m),5.05-4.93(2H,m),3.98-3.91(2H,m),3.57-3.39(4H,m),3.22-3.20(1H,m),3.12-3.05(2H,m),2.78-2.73(1H,m),2.66-2.58(1H,m),2.47-2.32(2H,m),2.05-2.03(1H,m),1.88-1.84(1H,m),1.60-1.48(1H,m),1.06-1.03(3H,m) [1266] 1H NMR (CD3OD) δ8.77-8.75 (2H, m), 8.44-8.42 (2H, m), 5.05-4.93 (2H, m), 3.98-3.91 (2H, m), 3.57-3.39 ( 4H, m), 3.22-3.20 (1H, m), 3.12-3.05 (2H, m), 2.78-2.73 (1H, m), 2.66-2.58 (1H, m), 2.47-2.32 (2H, m), 2.05-2.03 (1H, m), 1.88-1.84 (1H, m), 1.60-1.48 (1H, m), 1.06-1.03 (3H, m)

[1267] 质量(m/e)477(M+1) [1267] mass (m / e) 477 (M + 1)

[1268] 制备104:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1268] Preparation 104: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [2- pyridinyl - 4--4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1269] 利用制备57获得的47.0mg(0.140mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备91获得的45.0mg(0.127mmole)2-吡啶-4-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得65mg标题化合物,收率78%。 [1269] 57 was prepared using the obtained 47.0mg (0.140mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and preparation 91 45.0mg (0.127mmole) 2- pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-obtained d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 65mg, 78% yield.

[1270] 1H NMR(CDCl3)δ8.81(2H,brs),8.32-8.31(2H,m),5.81(1H,brs),4.98-4.96(1H,m),4.85-4.83(1H,m),4.23(1H,brs),3.95(1H,brs),3.81-3.73(3H,m),3.62-3.49(2H,m),3.16-3.10(2H,m),2.89-2.85(1H,m),2.62-2.55(3H,m),2.28(2H,m),1.42(9H,s) [1270] 1H NMR (CDCl3) δ8.81 (2H, brs), 8.32-8.31 (2H, m), 5.81 (1H, brs), 4.98-4.96 (1H, m), 4.85-4.83 (1H, m) , 4.23 (1H, brs), 3.95 (1H, brs), 3.81-3.73 (3H, m), 3.62-3.49 (2H, m), 3.16-3.10 (2H, m), 2.89-2.85 (1H, m) , 2.62-2.55 (3H, m), 2.28 (2H, m), 1.42 (9H, s)

[1271] 质量(m/e)599(M+1) [1271] mass (m / e) 599 (M + 1)

[1272] 实施例57:合成1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1272] Example 57: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1273] [1273]

[1274] 利用制备104获得的65mg(0.109mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得34.4mg标题化合物,收率64%。 [1274] using 65mg (0.109mmole) {(1S) -1 obtained in Preparation 104 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3 - [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl, in the same manner as in Example 22 to obtain 34.4mg of the title compound in 64% yield.

[1275] 1H NMR(CD3OD)δ8.77-8.75(2H,m),8.45-8.43(2H,m),5.06-4.86(2H,m),4.00-3.88(2H,m),3.85-3.78(2H,m),3.58-3.49(3H,m),3.21-3.11(2H,m),2.75-2.70(1H,m),2.64-2.54(3H,m),2.37-2.33(2H,m) [1275] 1H NMR (CD3OD) δ8.77-8.75 (2H, m), 8.45-8.43 (2H, m), 5.06-4.86 (2H, m), 4.00-3.88 (2H, m), 3.85-3.78 ( 2H, m), 3.58-3.49 (3H, m), 3.21-3.11 (2H, m), 2.75-2.70 (1H, m), 2.64-2.54 (3H, m), 2.37-2.33 (2H, m)

[1276] 质量(m/e)499(M+1) [1276] mass (m / e) 499 (M + 1)

[1277] 制备105:合成[(1S)-3-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [1277] Preparation 105: Synthesis of [(1S) -3- [2- (4- fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[1278] 利用制备51获得的38.0mg(0.120mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备92获得的38.0mg(0.109mmole)2-(4-氟苄基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得70mg标题化合物,收率96%。 [1278] 38.0mg 51 prepared using the obtained (0.120mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 38.0mg (0.109mmole) 92 preparation of 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [ 3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 70mg, yield 96%.

[1279] 1H NMR(CDCl3)δ7.34-7.32(2H,m),7.00-6.96(2H,m),5.86-5.85(1H,m),4.85-4.80(1H,m),4.73-4.61(1H,m),4.23-4.15(2H,m),3.86-3.83(1H,m),3.74-3.68(1H,m),3.56-3.47(2H,m),3.36-3.33(1H,m),3.06-2.95(3H,m),2.85-2.77(1H,m),2.50-2.83(4H,m),1.92(1H,brs),1.79(2H,brs),1.40-1.38(9H,m),0.99(3H,d,J=6.7Hz) [1279] 1H NMR (CDCl3) δ7.34-7.32 (2H, m), 7.00-6.96 (2H, m), 5.86-5.85 (1H, m), 4.85-4.80 (1H, m), 4.73-4.61 ( 1H, m), 4.23-4.15 (2H, m), 3.86-3.83 (1H, m), 3.74-3.68 (1H, m), 3.56-3.47 (2H, m), 3.36-3.33 (1H, m), 3.06-2.95 (3H, m), 2.85-2.77 (1H, m), 2.50-2.83 (4H, m), 1.92 (1H, brs), 1.79 (2H, brs), 1.40-1.38 (9H, m), 0.99 (3H, d, J = 6.7Hz)

[1280] 质量(m/e)608(M+1) [1280] mass (m / e) 608 (M + 1)

[1281] 实施例58:合成(5R)-1-{(2S)-2-氨基-4-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1281] Example 58: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1282] [1282]

[1283] 利用制备105获得的77mg(0.115mmole)[(1S)-3-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯,以实施例22的相同方式,获得49.7mg标题化合物,收率85%。 [1283] Preparation 105 using the obtained 77mg (0.115mmole) [(1S) -3- [2- (4- fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester, in the same manner as in Example 22 to obtain 49.7mg of the title compound in 85% yield.

[1284] 1H NMR(CD3OD)δ7.39-7.36(2H,m),7.04-7.00(2H,m),4.86-4.77(2H,m),4.28-4.27(2H,m),3.86-3.83(2H,m),3.50-3.37(4H,m),3.09-2.99(3H,m),2.73-2.66(1H,m),2.61-2.53(1H,m),2.43-2.29(2H,m),2.02-1.98(1H,m),1.85-1.82(1H,m),1.56-1.46(1H,m),1.03(3H,d,J=6.4Hz) [1284] 1H NMR (CD3OD) δ7.39-7.36 (2H, m), 7.04-7.00 (2H, m), 4.86-4.77 (2H, m), 4.28-4.27 (2H, m), 3.86-3.83 ( 2H, m), 3.50-3.37 (4H, m), 3.09-2.99 (3H, m), 2.73-2.66 (1H, m), 2.61-2.53 (1H, m), 2.43-2.29 (2H, m), 2.02-1.98 (1H, m), 1.85-1.82 (1H, m), 1.56-1.46 (1H, m), 1.03 (3H, d, J = 6.4Hz)

[1285] 质量(m/e)508(M+1) [1285] mass (m / e) 508 (M + 1)

[1286] 制备106:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1286] Preparation 106: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (4-fluorobenzyl) 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1287] 利用制备57获得的40.3mg(0.120mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备92获得的38.0mg(0.109mmole)2-(4-氟苄基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得66mg标题化合物,收率87%。 [1287] 57 was prepared using the obtained 40.3mg (0.120mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and obtained in preparation 92 38.0mg (0.109mmole) 2- (4- fluorobenzyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 66mg of the title compound in 87% yield.

[1288] 1H NMR(CDCl3)δ7.35-7.26(2H,m),7.00-6.97(2H,m),5.77-5.75(1H,m),4.85-4.80(1H,m),4.70-4.61(1H,m),4.24-4.18(3H,m),3.86-3.84(1H,m),3.76-3.67(2H,m),3.59-3.48(3H,m),3.07-2.97(2H,m),2.83-2.76(1H,m),2.57-2.49(3H,m),2.28-2.19(2H,m)1.40(9H,s) [1288] 1H NMR (CDCl3) δ7.35-7.26 (2H, m), 7.00-6.97 (2H, m), 5.77-5.75 (1H, m), 4.85-4.80 (1H, m), 4.70-4.61 ( 1H, m), 4.24-4.18 (3H, m), 3.86-3.84 (1H, m), 3.76-3.67 (2H, m), 3.59-3.48 (3H, m), 3.07-2.97 (2H, m), 2.83-2.76 (1H, m), 2.57-2.49 (3H, m), 2.28-2.19 (2H, m) 1.40 (9H, s)

[1289] 质量(m/e)630(M+1-Boc) [1289] mass (m / e) 630 (M + 1-Boc)

[1290] 实施例59:合成1-{(2S)-2-氨基-4-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1290] Example 59: Synthesis of 1 - {(2S) -2- amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1291] [1291]

[1292] 利用制备106获得的66.0mg(0.105mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得44.4mg标题化合物,收率80%。 [1292] prepared using 106 66.0mg (0.105mmole) {(1S) -1 obtained - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} amino acid tert - butyl ester, in the same manner as in Example 22 to obtain 44.4mg of the title compound in 80% yield.

[1293] 1H NMR(CD3OD)δ7.39-7.36(2H,m),7.04-7.00(2H,m),4.89-4.81(2H,m),4.28-4.27(2H,m),3.88-3.77(4H,m),3.53-3.47(3H,m),3.09-2.99(2H,m),2.66-2.61(1H,m),2.58-2.49(3H,m),2.40-2.29(2H,m) [1293] 1H NMR (CD3OD) δ7.39-7.36 (2H, m), 7.04-7.00 (2H, m), 4.89-4.81 (2H, m), 4.28-4.27 (2H, m), 3.88-3.77 ( 4H, m), 3.53-3.47 (3H, m), 3.09-2.99 (2H, m), 2.66-2.61 (1H, m), 2.58-2.49 (3H, m), 2.40-2.29 (2H, m)

[1294] 质量(m/e)530(M+1) [1294] mass (m / e) 530 (M + 1)

[1295] 制备107:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1295] Preparation 107: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1296] 利用制备51的43.0mg(0.137mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备95获得的40.0mg(0.124mmole)2-(3-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得75.0mg标题化合物,收率94%。 [1296] using 43.0mg (0.137mmole) of Preparation 51 (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxo-piperidin - 1- yl] butanoic acid obtained in preparation 95 and 40.0mg (0.124mmole) 2- (3- thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 75.0mg of the title compound in 94% yield.

[1297] 1H NMR(CDCl3)δ8.38-8.37(1H,m),7.93-7.91(1H,m),7.43-7.40(1H,m),5.90-5.88(1H,m),5.33(1H,s),4.92-4.74(1H,m),4.23-4.13(1H,m),3.98-3.92(1H,m),3.84-3.81(1H,m),3.73-3.51(2H,m),3.42-3.28(1H,m),3.13-3.04(3H,m),2.93-2.87(1H,m),2.59-2.54(1H,m),2.48-2.32(2H,m),2.00-1.84(3H,m),1.46-1.44(9H,m)1.04-1.03(3H,m) [1297] 1H NMR (CDCl3) δ8.38-8.37 (1H, m), 7.93-7.91 (1H, m), 7.43-7.40 (1H, m), 5.90-5.88 (1H, m), 5.33 (1H, s), 4.92-4.74 (1H, m), 4.23-4.13 (1H, m), 3.98-3.92 (1H, m), 3.84-3.81 (1H, m), 3.73-3.51 (2H, m), 3.42- 3.28 (1H, m), 3.13-3.04 (3H, m), 2.93-2.87 (1H, m), 2.59-2.54 (1H, m), 2.48-2.32 (2H, m), 2.00-1.84 (3H, m ), 1.46-1.44 (9H, m) 1.04-1.03 (3H, m)

[1298] 质量(m/e)582(M+1) [1298] mass (m / e) 582 (M + 1)

[1299] 实施例60:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [1299] Example 60: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5 , 8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[1300] [1300]

[1301] 利用制备107获得的75.0mg(0.129mmole){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得54.4mg标题化合物,收率88%。 75.0mg [1301] 107 was prepared using the obtained (0.129mmole) {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo substituting 3- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester, in the same manner as Example 22 to give 54.4mg of the title compound in 88% yield.

[1302] 1H NMR(CD3OD)δ8.41-8.40(1H,m),7.90-7.88(1H,m),7.54-7.52(1H,m),4.97-4.86(2H,m),3.96-3.86(2H,m),3.67-3.63(1H,m),3.57-3.45(2H,m),3.42-3.37(1H,m),3.13-3.03(3H,m),2.80-2.76(1H,m),2.68-2.59(1H,m),2.46-2.32(2H,m),2.01(1H,brs),1.84-1.82(1H,m),1.58-1.51(1H,m),1.06-1.03(3H,m) [1302] 1H NMR (CD3OD) δ8.41-8.40 (1H, m), 7.90-7.88 (1H, m), 7.54-7.52 (1H, m), 4.97-4.86 (2H, m), 3.96-3.86 ( 2H, m), 3.67-3.63 (1H, m), 3.57-3.45 (2H, m), 3.42-3.37 (1H, m), 3.13-3.03 (3H, m), 2.80-2.76 (1H, m), 2.68-2.59 (1H, m), 2.46-2.32 (2H, m), 2.01 (1H, brs), 1.84-1.82 (1H, m), 1.58-1.51 (1H, m), 1.06-1.03 (3H, m )

[1303] 质量(m/e)482(M+1) [1303] mass (m / e) 482 (M + 1)

[1304] 制备108:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1304] Preparation 108: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [2- (3 - thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1305] 利用制备57获得的43mg(0.137mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备93获得的40.0mg(0.124mmole)2-(3-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得66.0mg标题化合物,收率80%。 [1305] 57 was prepared using the obtained 43mg (0.137mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 yl) butyric acid and 40.0mg (0.124mmole) obtained in preparation 93 2- (3-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 66.0mg, 80% yield.

[1306] 1H NMR(CD3OD)δ8.35-8.34(1H,m),7.89-7.87(1H,m),7.40-7.37(1H,m),5.79-5.77(1H,m),4.88(1H,s),4.80-4.69(1H,m),4.23(1H,brs),3.92-3.89(1H,m),3.78-3.66(3H,m),3.60-3.55(2H,m),3.08-3.01(2H,m),2.87-2.83(1H,m),2.62-2.53(3H,m),2.35-2.23(2H,m),1.42-1.41(9H,m) [1306] 1H NMR (CD3OD) δ8.35-8.34 (1H, m), 7.89-7.87 (1H, m), 7.40-7.37 (1H, m), 5.79-5.77 (1H, m), 4.88 (1H, s), 4.80-4.69 (1H, m), 4.23 (1H, brs), 3.92-3.89 (1H, m), 3.78-3.66 (3H, m), 3.60-3.55 (2H, m), 3.08-3.01 ( 2H, m), 2.87-2.83 (1H, m), 2.62-2.53 (3H, m), 2.35-2.23 (2H, m), 1.42-1.41 (9H, m)

[1307] 质量(m/e)604(M+1) [1307] mass (m / e) 604 (M + 1)

[1308] 实施例61:合成1-{(2S)-2-氨基-4-氧代-4-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1308] Example 61: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1309] [1309]

[1310] 利用制备108获得的66mg(0.109mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得44.0mg标题化合物,收率80%。 [1310] prepared using 108 66mg (0.109mmole) {(1S) -1 obtained - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3 - [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamate - butyl ester in the same manner as in Example 22 to obtain 44.0mg of the title compound in 80% yield.

[1311] 1H NMR(CD3OD)δ8.41-8.40(1H,m),7.90-7.88(1H,m),7.55-7.52(1H,m),4.95-4.89(2H,m),3.88-3.79(4H,m),3.58-3.53(1H,m),3.50-3.45(2H,m),3.12-3.02(2H,m),2.74-2.68(1H,m),2.62-2.51(3H,m),2.40-2.33(2H,m) [1311] 1H NMR (CD3OD) δ8.41-8.40 (1H, m), 7.90-7.88 (1H, m), 7.55-7.52 (1H, m), 4.95-4.89 (2H, m), 3.88-3.79 ( 4H, m), 3.58-3.53 (1H, m), 3.50-3.45 (2H, m), 3.12-3.02 (2H, m), 2.74-2.68 (1H, m), 2.62-2.51 (3H, m), 2.40-2.33 (2H, m)

[1312] 质量(m/e)504(M+1) [1312] mass (m / e) 504 (M + 1)

[1313] 制备109:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1313] Preparation 109: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1314] 利用制备51获得的43.0mg(0.137mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备94获得的40.0mg(0.124mmole)2-(2-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得80.0mg标题化合物,收率100%。 [1314] 43.0mg 51 prepared using the obtained (0.137mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 40.0mg (0.124mmole) 94 preparation of 2- (2-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3 , 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 80.0mg of the title compound, yield 100%.

[1315] 1H NMR(CDCl3)δ8.05-8.04(1H,m),7.52-7.51(1H,m),7.16-7.13(1H,m),5.89(1H,brs),4.87(1H,s),4.76-4.69(1H,m),4.25-4.18(1H,m),3.91-3.88(1H,m),3.80-3.77(1H,m),3.67-3.51(3H,m),3.38-3.27(1H,m),3.11-2.99(3H,m),2.89-2.83(1H,m),2.56-2.28(3H,m),2.01-1.91(1H,m),1.85-1.81(1H,m),1.42-1.41(9H,m),1.00(3H,d,J=6.8Hz) [1315] 1H NMR (CDCl3) δ8.05-8.04 (1H, m), 7.52-7.51 (1H, m), 7.16-7.13 (1H, m), 5.89 (1H, brs), 4.87 (1H, s) , 4.76-4.69 (1H, m), 4.25-4.18 (1H, m), 3.91-3.88 (1H, m), 3.80-3.77 (1H, m), 3.67-3.51 (3H, m), 3.38-3.27 ( 1H, m), 3.11-2.99 (3H, m), 2.89-2.83 (1H, m), 2.56-2.28 (3H, m), 2.01-1.91 (1H, m), 1.85-1.81 (1H, m), 1.42-1.41 (9H, m), 1.00 (3H, d, J = 6.8Hz)

[1316] 质量(m/e)582(M+1) [1316] mass (m / e) 582 (M + 1)

[1317] 实施例62:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [1317] Example 62: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5 , 8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[1318] [1318]

[1319] 利用制备109获得的80.0mg(0.138mmole){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得58.6mg标题化合物,收率89%。 [1319] prepared using 109 80.0mg (0.138mmole) {(1S) -1 obtained - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo -3- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester, in the same manner as Example 22 to give 58.6mg of the title compound in 89% yield.

[1320] 1H NMR(CD3OD)δ8.04-8.03(1H,m),7.68-7.66(1H,m),7.21-7.18(1H,m),4.93-4.82(2H,m),3.93-3.86(2H,m),3.70-3.63(1H,m),3.56-3.44(2H,m),3.42-3.37(1H,m),3.10-3.00(3H,m),2.79-2.74(1H,m),2.66-2.58(1H,m),2.45-2.32(2H,m),2.05-2.00(1H,m),1.85-1.81(1H,m),1.58-1.50(1H,m),1.05-1.03(3H,m) [1320] 1H NMR (CD3OD) δ8.04-8.03 (1H, m), 7.68-7.66 (1H, m), 7.21-7.18 (1H, m), 4.93-4.82 (2H, m), 3.93-3.86 ( 2H, m), 3.70-3.63 (1H, m), 3.56-3.44 (2H, m), 3.42-3.37 (1H, m), 3.10-3.00 (3H, m), 2.79-2.74 (1H, m), 2.66-2.58 (1H, m), 2.45-2.32 (2H, m), 2.05-2.00 (1H, m), 1.85-1.81 (1H, m), 1.58-1.50 (1H, m), 1.05-1.03 (3H , m)

[1321] 质量(m/e)482(M+1) [1321] mass (m / e) 482 (M + 1)

[1322] 制备110:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1322] Preparation 110: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [2- (2 - thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1323] 利用制备57获得的43.0mg(0.137mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备94获得的40.0mg(0.124mmole)2-(2-噻吩基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得29.0mg标题化合物,收率35%。 [1323] 57 was prepared using the obtained 43.0mg (0.137mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and 94 obtained in preparation 40.0mg (0.124mmole) 2- (2- thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- -d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 29.0mg of the title compound in 35% yield.

[1324] 1H NMR(CDCl3)δ8.10-8.09(1H,m),7.57-7.55(1H,m),7.21-7.18(1H,m),5.83-5.81(1H,m),4.95-4.82(1H,m),4.81-4.72(1H,m),4.30-4.20(1H,m),3.95-3.93(1H,m),3.82-3.73(3H,m),3.63-3.62(2H,m),3.11-3.04(2H,m),2.90-2.86(1H,m),2.66-2.57(3H,m),2.36-2.27(2H,m),1.46-1.45(9H,m) [1324] 1H NMR (CDCl3) δ8.10-8.09 (1H, m), 7.57-7.55 (1H, m), 7.21-7.18 (1H, m), 5.83-5.81 (1H, m), 4.95-4.82 ( 1H, m), 4.81-4.72 (1H, m), 4.30-4.20 (1H, m), 3.95-3.93 (1H, m), 3.82-3.73 (3H, m), 3.63-3.62 (2H, m), 3.11-3.04 (2H, m), 2.90-2.86 (1H, m), 2.66-2.57 (3H, m), 2.36-2.27 (2H, m), 1.46-1.45 (9H, m)

[1325] 质量(m/e)604(M+1) [1325] mass (m / e) 604 (M + 1)

[1326] 实施例63:合成1-{(2S)-2-氨基-4-氧代-4-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1326] Example 63: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1327] [1327]

[1328] 利用制备110获得的29mg(0.048mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得20.3mg标题化合物,收率84%。 [1328] Preparation 110 using the obtained 29mg (0.048mmole) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3 - [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamate - butyl ester in the same manner as Example 22 to give the title compound 20.3mg, yield 84%.

[1329] 1H NMR(CD3OD)δ8.06-8.05(1H,m),7.67-7.66(1H,m),7.21-7.19(1H,m),4.94-4.82(2H,m),3.94-3.78(4H,m),3.54-3.48(3H,m),3.11-3.02(2H,m),2.74-2.69(1H,m),2.62-2.56(3H,m),2.40-2.35(2H,m) [1329] 1H NMR (CD3OD) δ8.06-8.05 (1H, m), 7.67-7.66 (1H, m), 7.21-7.19 (1H, m), 4.94-4.82 (2H, m), 3.94-3.78 ( 4H, m), 3.54-3.48 (3H, m), 3.11-3.02 (2H, m), 2.74-2.69 (1H, m), 2.62-2.56 (3H, m), 2.40-2.35 (2H, m)

[1330] 质量(m/e)504(M+1) [1330] mass (m / e) 504 (M + 1)

[1331] 制备111:合成{(1S)-3-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}3-氧代丙基}氨基甲酸叔-丁酯 [1331] Preparation 111: Synthesis of {(1S) -3- [2- (2- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} 3-oxo-propyl} carbamic acid tert - butyl ester

[1332] 利用制备51获得的45.3mg(0.144mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备95获得的40.0mg(0.131mmole)2-(2-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得70.0mg标题化合物,收率86%。 [1332] 45.3mg 51 prepared using the obtained (0.144mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid obtained in preparation 95 and 40.0mg (0.131mmole) 2- (2- furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3 , 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 70.0mg of the title compound in 86% yield.

[1333] 1H NMR(CDCl3)δ7.68-7.65(1H,m),7.43-7.38(1H,m),6.61-6.59(1H,m),5.91-5.89(1H,m),4.98-4.87(1H,m),4.85-4.74(1H,m),4.20(1H,brs),3.94-3.89(1H,m),3.82-3.78(1H,m),3.62-3.48(3H,m),3.44-3.36(1H,m),3.08-3.01(3H,m),2.88-2.81(1H,m),2.58-2.28(3H,m),2.04(1H,brs),1.84-1.82(1H,m),1.42-1.40(9H,m),1.00(3H,d,J=6.4Hz) [1333] 1H NMR (CDCl3) δ7.68-7.65 (1H, m), 7.43-7.38 (1H, m), 6.61-6.59 (1H, m), 5.91-5.89 (1H, m), 4.98-4.87 ( 1H, m), 4.85-4.74 (1H, m), 4.20 (1H, brs), 3.94-3.89 (1H, m), 3.82-3.78 (1H, m), 3.62-3.48 (3H, m), 3.44- 3.36 (1H, m), 3.08-3.01 (3H, m), 2.88-2.81 (1H, m), 2.58-2.28 (3H, m), 2.04 (1H, brs), 1.84-1.82 (1H, m), 1.42-1.40 (9H, m), 1.00 (3H, d, J = 6.4Hz)

[1334] 质量(m/e)566(M+1-Boc) [1334] mass (m / e) 566 (M + 1-Boc)

[1335] 实施例64:合成(5R)-1-{(2S)-2-氨基-4-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1335] Example 64: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1336] [1336]

[1337] 利用制备111获得的70.0mg(0.124mmole){(1S)-3-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得57.7mg标题化合物,收率93%。 [1337] Preparation 111 obtained by using 70.0mg (0.124mmole) {(1S) -3- [2- (2- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} amino-3-oxopropyl} acid tert - butyl ester, in the same manner as in Example 22 to obtain 57.7mg of the title compound in 93% yield.

[1338] 1H NMR(CD3OD)δ7.81(1H,m),7.43-7.42(1H,m),6.70-6.68(1H,m),4.99-4.87(2H,m),3.98-3.83(5H,m),3.59-3.55(1H,m),3.17-3.11(2H,m),3.04-2.98(2H,m),2.88-2.79(1H,m),2.48-2.41(2H,m),2.10-2.06(1H,m),1.90-1.85(1H,m),1.60-1.53(1H,m),1.06(3H,d,J=6.8Hz) [1338] 1H NMR (CD3OD) δ7.81 (1H, m), 7.43-7.42 (1H, m), 6.70-6.68 (1H, m), 4.99-4.87 (2H, m), 3.98-3.83 (5H, m), 3.59-3.55 (1H, m), 3.17-3.11 (2H, m), 3.04-2.98 (2H, m), 2.88-2.79 (1H, m), 2.48-2.41 (2H, m), 2.10- 2.06 (1H, m), 1.90-1.85 (1H, m), 1.60-1.53 ​​(1H, m), 1.06 (3H, d, J = 6.8Hz)

[1339] 质量(m/e)466(M+1) [1339] mass (m / e) 466 (M + 1)

[1340] 制备112:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1340] Preparation 112: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (2-furyl) - 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1341] 利用制备57获得的48mg(0.144mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备95获得的40.0mg(0.131mmole)2-(2-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得75.0mg标题化合物,收率89%。 [1341] 57 was prepared using the obtained 48mg (0.144mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 yl) butanoic acid obtained in preparation 95 and 40.0mg (0.131mmole) 2- (2- furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 75.0mg of the title compound in 89% yield.

[1342] 1H NMR(CDCl3)δ7.64(1H,m),7.40-7.38(1H,m),6.60-6.56(1H,m),5.82-5.79(1H,m),4.95-4.88(1H,m),4.80-4.71(1H,m),4.20(1H,brs),3.92-3.85(1H,m),3.78-3.68(3H,m),3.60-3.50(1H,m),3.10-3.00(2H,m),2.85-2.78(1H,m),2.60-2.50(3H,m),2.30-2.20(2H,m),1.40(9H,s) [1342] 1H NMR (CDCl3) δ7.64 (1H, m), 7.40-7.38 (1H, m), 6.60-6.56 (1H, m), 5.82-5.79 (1H, m), 4.95-4.88 (1H, m), 4.80-4.71 (1H, m), 4.20 (1H, brs), 3.92-3.85 (1H, m), 3.78-3.68 (3H, m), 3.60-3.50 (1H, m), 3.10-3.00 ( 2H, m), 2.85-2.78 (1H, m), 2.60-2.50 (3H, m), 2.30-2.20 (2H, m), 1.40 (9H, s)

[1343] 质量(m/e)588(M+1) [1343] mass (m / e) 588 (M + 1)

[1344] 实施例65:合成1-{(2S)-2-氨基-4-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氧吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1344] Example 65: Synthesis of 1 - {(2S) -2- amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dioxo-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1345] [1345]

[1346] 利用制备112获得的75mg(0.128mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得48.9mg标题化合物,收率73%。 [1346] Preparation 112 using the obtained 75mg (0.128mmole) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- ( 2-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester in the same manner as in Example 22 to obtain 48.9mg of the title compound in 73% yield.

[1347] 1H NMR(CD3OD)δ7.81-7.80(1H,m),7.43-7.42(1H,m),6.70-6.68(1H,m),4.98-4.88(2H,m),3.98-3.75(6H,m),3.61-3.50(1H,m),3.20-3.10(1H,m)3.07-2.99(2H,m),2.91-2.83(1H,m),2.69-2.62(2H,m),2.44-2.34(2H,m) [1347] 1H NMR (CD3OD) δ7.81-7.80 (1H, m), 7.43-7.42 (1H, m), 6.70-6.68 (1H, m), 4.98-4.88 (2H, m), 3.98-3.75 ( 6H, m), 3.61-3.50 (1H, m), 3.20-3.10 (1H, m) 3.07-2.99 (2H, m), 2.91-2.83 (1H, m), 2.69-2.62 (2H, m), 2.44 -2.34 (2H, m)

[1348] 质量(m/e)488(M+1) [1348] mass (m / e) 488 (M + 1)

[1349] 制备113:合成[(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}3-氧代丙基]氨基甲酸叔-丁酯 [1349] Preparation 113: Synthesis of [(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} 3-oxopropyl] carbamic acid tert - butyl ester

[1350] 利用制备51获得的49.0mg(0.155mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备96获得的43.0mg(0.141mmole)2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得80.0mg标题化合物,收率91%。 [1350] 49.0mg 51 prepared using the obtained (0.155mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid obtained in 96 preparation and 43.0mg (0.141mmole) 2- (3- furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3 , 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 80.0mg of the title compound in 91% yield.

[1351] 1H NMR(CDCl3)δ8.25(1H,s),7.49-7.48(1H,m),7.04-7.03(1H,m),5.87-5.83(1H,m),4.85(1H,s),4.74-4.67(1H,m),4.18-4.13(1H,m),3.89-3.87(1H,m),3.80-3.75(1H,m),3.62-3.47(3H,m),3.40-3.30(1H,m),3.07-2.95(3H,m),2.87-2.82(1H,m),2.52-2.31(3H,m),1.93(1H,brs),1.80(1H,brs),1.41-1.39(9H,m),0.99(3H,d,J=6.9Hz) [1351] 1H NMR (CDCl3) δ8.25 (1H, s), 7.49-7.48 (1H, m), 7.04-7.03 (1H, m), 5.87-5.83 (1H, m), 4.85 (1H, s) , 4.74-4.67 (1H, m), 4.18-4.13 (1H, m), 3.89-3.87 (1H, m), 3.80-3.75 (1H, m), 3.62-3.47 (3H, m), 3.40-3.30 ( 1H, m), 3.07-2.95 (3H, m), 2.87-2.82 (1H, m), 2.52-2.31 (3H, m), 1.93 (1H, brs), 1.80 (1H, brs), 1.41-1.39 ( 9H, m), 0.99 (3H, d, J = 6.9Hz)

[1352] 质量(m/e)566(M+1) [1352] mass (m / e) 566 (M + 1)

[1353] 实施例66:合成(5R)-1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1353] Example 66: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1354] [1354]

[1355] 利用制备113获得的80.0mg(0.076mmole)[(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}3-氧代丙基]氨基甲酸叔-丁酯,以实施例22的相同方式,获得68.1mg标题化合物,收率95%。 80.0mg [1355] 113 was prepared using the obtained (0.076mmole) [(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} 3-oxopropyl] amino acid tert - butyl ester, in the same manner as in Example 22 to obtain 68.1mg of the title compound in 95% yield.

[1356] 1H NMR(CD3OD)δ8.53(1H,s),7.65-7.64(1H,m),7.08(1H,s),4.97-4.86(2H,m),3.96-3.83(4H,m),3.69-3.59(1H,m),3.43-3.37(1H,m)3.20-3.15(4H,m),2.88-2.75(1H,m),2.50-2.40(2H,m),2.06(1H,brs),1.88-1.84(1H,m),1.60-1.51(1H,m),1.07(3H,d,J=6.4Hz) [1356] 1H NMR (CD3OD) δ8.53 (1H, s), 7.65-7.64 (1H, m), 7.08 (1H, s), 4.97-4.86 (2H, m), 3.96-3.83 (4H, m) , 3.69-3.59 (1H, m), 3.43-3.37 (1H, m) 3.20-3.15 (4H, m), 2.88-2.75 (1H, m), 2.50-2.40 (2H, m), 2.06 (1H, brs ), 1.88-1.84 (1H, m), 1.60-1.51 (1H, m), 1.07 (3H, d, J = 6.4Hz)

[1357] 质量(m/e)466(M+1) [1357] mass (m / e) 466 (M + 1)

[1358] 制备114:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1358] Preparation 114: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (3-furyl) - 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1359] 利用制备57的52mg(0.155mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备96获得的43.0mg(0.141mmole)2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得85.0mg标题化合物,收率93%。 [1359] is prepared using 52mg 57 (0.155mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin-1-yl ) butyric acid and 96 obtained in preparation 43.0mg (0.141mmole) 2- (3- furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d ] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 85.0mg of the title compound in 93% yield.

[1360] 1H NMR(CDCl3)δ8.26(1H,s),7.49(1H,s),7.04-7.03(1H,m),5.77(1H,brs),4.84(1H,s),4.75-4.70(1H,m),4.20(1H,brs),3.88(1H,brs),3.75-3.68(3H,m),3.59-3.55(2H,m),3.06-2.99(2H,m),2.83-2.80(1H,m),2.58-2.53(3H,m),2.25(2H,m),1.41-1.40(9H,m) [1360] 1H NMR (CDCl3) δ8.26 (1H, s), 7.49 (1H, s), 7.04-7.03 (1H, m), 5.77 (1H, brs), 4.84 (1H, s), 4.75-4.70 (1H, m), 4.20 (1H, brs), 3.88 (1H, brs), 3.75-3.68 (3H, m), 3.59-3.55 (2H, m), 3.06-2.99 (2H, m), 2.83-2.80 (1H, m), 2.58-2.53 (3H, m), 2.25 (2H, m), 1.41-1.40 (9H, m)

[1361] 质量(m/e)588(M+1) [1361] mass (m / e) 588 (M + 1)

[1362] 实施例67:合成1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氧吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1362] Example 67: Synthesis of 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dioxo-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1363] [1363]

[1364] 利用制备114获得的85mg(0.145mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得68.8mg标题化合物,收率91%。 [1364] using 85mg (0.145mmole) {(1S) -1 obtained in Preparation 114 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- ( 3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester in the same manner as in Example 22 to obtain 68.8mg of the title compound in 91% yield.

[1365] 1H NMR(CD3OD)δ8.36(1H,s),7.65-7.64(1H,m),7.09(1H,s),4.97-4.80(2H,m),3.98-3.79(6H,m),3.54-3.51(1H,m),3.15-3.01(3H,m),2.89-2.83(1H,m),2.65-2.61(2H,m),2.42-2.36(2H,m) [1365] 1H NMR (CD3OD) δ8.36 (1H, s), 7.65-7.64 (1H, m), 7.09 (1H, s), 4.97-4.80 (2H, m), 3.98-3.79 (6H, m) , 3.54-3.51 (1H, m), 3.15-3.01 (3H, m), 2.89-2.83 (1H, m), 2.65-2.61 (2H, m), 2.42-2.36 (2H, m)

[1366] 质量(m/e)488(M+1) [1366] mass (m / e) 488 (M + 1)

[1367] 制备115:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1367] Preparation 115: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- (lH-pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl

[1368] 利用制备51获得的27.3mg(0.087mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备98获得的24.0mg(0.079mmole)2-(1H-吡咯-2-基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得43.0mg标题化合物,收率88%。 [1368] 27.3mg 51 prepared using the obtained (0.087mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 24.0mg (0.079mmole) obtained in preparation 98 2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyridine and [3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 43.0mg of the title compound in 88% yield.

[1369] 1H NMR(CDCl3)δ9.55(1H,brs),7.20-7.18(1H,m),7.04(1H,s),6.39(1H,s),5.91-5.88(1H,m),4.86(1H,s),4.80-4.69(1H,m),4.23-4.17(1H,m),3.92-3.90(1H,m),3.81-3.79(1H,m),3.66-3.54(1H,m),3.66-3.54(2H,m),3.41-3.38(1H,m),3.14-2.87(4H,m),2.57-2.37(3H,m),1.98(1H,m),1.85(1H,m),1.45-1.44(9H,m),1.06-1.03(3H,m) [1369] 1H NMR (CDCl3) δ9.55 (1H, brs), 7.20-7.18 (1H, m), 7.04 (1H, s), 6.39 (1H, s), 5.91-5.88 (1H, m), 4.86 (1H, s), 4.80-4.69 (1H, m), 4.23-4.17 (1H, m), 3.92-3.90 (1H, m), 3.81-3.79 (1H, m), 3.66-3.54 (1H, m) , 3.66-3.54 (2H, m), 3.41-3.38 (1H, m), 3.14-2.87 (4H, m), 2.57-2.37 (3H, m), 1.98 (1H, m), 1.85 (1H, m) , 1.45-1.44 (9H, m), 1.06-1.03 (3H, m)

[1370] 质量(m/e)565(M+1) [1370] mass (m / e) 565 (M + 1)

[1371] 实施例68:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [1371] Example 68: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo -4- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl ) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[1372] [1372]

[1373] 利用制备115获得的43.0mg(0.076mmole){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得35.2mg标题化合物,收率86%。 [1373] Preparation 115 obtained by using 43.0mg (0.076mmole) {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo Generation -3- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester, in the same manner as Example 22 to obtain 35.2mg of the title compound in 86% yield.

[1374] 1H NMR(CD3OD)δ7.10-7.09(1H,m),7.03-7.00(1H,m),6.28-6.26(1H,m),4.92-4.83(2H,m),3.96-3.93(2H,m),3.86-3.83(2H,m),3.77-3.66(1H,m),3.41-3.36(1H,m),3.23-2.83(5H,m),2.45-2.41(2H,m),2.06(1H,brs),1.86(1H,m),1.57-1.30(1H,m),1.05(3H,d,J=6.8Hz) [1374] 1H NMR (CD3OD) δ7.10-7.09 (1H, m), 7.03-7.00 (1H, m), 6.28-6.26 (1H, m), 4.92-4.83 (2H, m), 3.96-3.93 ( 2H, m), 3.86-3.83 (2H, m), 3.77-3.66 (1H, m), 3.41-3.36 (1H, m), 3.23-2.83 (5H, m), 2.45-2.41 (2H, m), 2.06 (1H, brs), 1.86 (1H, m), 1.57-1.30 (1H, m), 1.05 (3H, d, J = 6.8Hz)

[1375] 质量(m/e)465(M+1) [1375] mass (m / e) 465 (M + 1)

[1376] 制备116:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1376] Preparation 116: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo -3- [2- (1H - pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1377] 利用制备57获得的20.0mg(0.087mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备98获得的24.0mg(0.079mmole)2-(1H-吡咯-2-基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得37.0mg标题化合物,收率73%。 [1377] 57 was prepared using the obtained 20.0mg (0.087mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and 98 obtained in preparation 24.0mg (0.079mmole) 2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [ 3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 37.0mg of the title compound in 73% yield.

[1378] 1H NMR(CDCl3)δ9.55(1H,brs),7.20-7.18(1H,m),7.04(1H,s),6.40-6.38(1H,m),5.83-5.81(1H,m),4.86(1H,s),4.77-4.67(1H,m),4.27(1H,brs),3.94-3.90(1H,m),3.83-3.73(3H,m),3.64-3.62(2H,m),3.07-3.00(2H,m),2.90-2.80(1H,m),2.65-2.58(3H,m),2.36-2.27(2H,m),1.46-1.45(9H,s), [1378] 1H NMR (CDCl3) δ9.55 (1H, brs), 7.20-7.18 (1H, m), 7.04 (1H, s), 6.40-6.38 (1H, m), 5.83-5.81 (1H, m) , 4.86 (1H, s), 4.77-4.67 (1H, m), 4.27 (1H, brs), 3.94-3.90 (1H, m), 3.83-3.73 (3H, m), 3.64-3.62 (2H, m) , 3.07-3.00 (2H, m), 2.90-2.80 (1H, m), 2.65-2.58 (3H, m), 2.36-2.27 (2H, m), 1.46-1.45 (9H, s),

[1379] 质量(m/e)587(M+1) [1379] mass (m / e) 587 (M + 1)

[1380] 实施例69:合成1-{(2S)-2-氨基-4-氧代-4-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1380] Example 69: Synthesis of 1 - {(2S) -2- amino-4-oxo -4- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5, 8- dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1381] [1381]

[1382] 利用制备116获得的37mg(0.063mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得34.9mg标题化合物,收率99%。 [1382] Preparation 116 using the obtained 37mg (0.063mmole) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3 - [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester, in the same manner as in Example 22 to obtain 34.9mg of the title compound in 99% yield.

[1383] 1H NMR(CD3OD)δ7.10-7.08(1H,m),7.03-7.02(1H,m),6.28-6.26(1H,m),4.93-4.82(2H,m),3.97-3.74(6H,m),3.70-3.54(1H,m),3.09-2.87(4H,m),2.68-2.58(2H,m),2.43-2.35(2H,m) [1383] 1H NMR (CD3OD) δ7.10-7.08 (1H, m), 7.03-7.02 (1H, m), 6.28-6.26 (1H, m), 4.93-4.82 (2H, m), 3.97-3.74 ( 6H, m), 3.70-3.54 (1H, m), 3.09-2.87 (4H, m), 2.68-2.58 (2H, m), 2.43-2.35 (2H, m)

[1384] 质量(m/e)488(M+1) [1384] mass (m / e) 488 (M + 1)

[1385] 制备117:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1385] Preparation 117: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1386] 利用制备45获得的40.0mg(0.127mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备97获得的40.0mg(0.126mmole)2-吡啶-3-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得65.6mg标题化合物,收率90%。 40.0mg [1386] obtained in Preparation 45 using (0.127mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid obtained in 97 preparation and 40.0mg (0.126mmole) 2- pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, 4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 65.6mg of the title compound in 90% yield.

[1387] 1H NMR(CDCl3)δ9.68(1H,s),8.78-8.76(2H,m),7.50-7.44(1H,m),5.94-5.92(1H,m),5.04-4.81(2H,m),4.24(1H,brs),3.98-3.95(1H,m),3.87-3.84(1H,m),3.62-3.52(2H,m),3.44-3.39(1H,m),3.18-3.11(3H,m),2.89(1H,m),2.61-2.57(1H,m),2.45-2.35(3H,m),1.98(1H,brs),1.84(1H,brs),1.46-1.44(9H,m),1.04(3H,d,J=8.0Hz) [1387] 1H NMR (CDCl3) δ9.68 (1H, s), 8.78-8.76 (2H, m), 7.50-7.44 (1H, m), 5.94-5.92 (1H, m), 5.04-4.81 (2H, m), 4.24 (1H, brs), 3.98-3.95 (1H, m), 3.87-3.84 (1H, m), 3.62-3.52 (2H, m), 3.44-3.39 (1H, m), 3.18-3.11 ( 3H, m), 2.89 (1H, m), 2.61-2.57 (1H, m), 2.45-2.35 (3H, m), 1.98 (1H, brs), 1.84 (1H, brs), 1.46-1.44 (9H, m), 1.04 (3H, d, J = 8.0Hz)

[1388] 质量(m/e)577(M+1) [1388] mass (m / e) 577 (M + 1)

[1389] 实施例70:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2酮 [1389] Example 70: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5, 8- dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidine-2-one

[1390] [1390]

[1391] 利用制备117获得的65.6mg(0.114mmole){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得59.7mg标题化合物,收率95%。 [1391] using 65.6mg (0.114mmole) {(1S) -1 obtained in Preparation 117 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo -3- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} amino acid tert - butyl ester, in the same manner as in Example 22 to obtain 59.7mg of the title compound in 95% yield.

[1392] 1H NMR(CD3OD)δ9.78(1H,s),9.62(1H,d,8.4Hz),9.07(1H,d,5.2Hz),8.35-8.32(1H,m),5.12-5.01(2H,m),4.03-3.95(3H,m),3.86-3.75(1H,m),3.70-3.59(1H,m),3.44-3.37(1H,m),3.28(1H,brs),3.19-2.96(2H,m),2.95-2.90(2H,m),2.45-2.42(2H,m),2.17(1H,brs),1.89-1.84(1H,m),1.59-1.54(1H,m),1.07(3H,d,J=6.4Hz) [1392] 1H NMR (CD3OD) δ9.78 (1H, s), 9.62 (1H, d, 8.4Hz), 9.07 (1H, d, 5.2Hz), 8.35-8.32 (1H, m), 5.12-5.01 ( 2H, m), 4.03-3.95 (3H, m), 3.86-3.75 (1H, m), 3.70-3.59 (1H, m), 3.44-3.37 (1H, m), 3.28 (1H, brs), 3.19- 2.96 (2H, m), 2.95-2.90 (2H, m), 2.45-2.42 (2H, m), 2.17 (1H, brs), 1.89-1.84 (1H, m), 1.59-1.54 (1H, m), 1.07 (3H, d, J = 6.4Hz)

[1393] 质量(m/e)477(M+1) [1393] mass (m / e) 477 (M + 1)

[1394] 制备118:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1394] Preparation 118: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [2- pyridinyl - 3--4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1395] 利用制备57获得的42.4mg(0.127mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备97获得的40.0mg(0.126mmole)2-吡啶-3-基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐,以制备45的相同方式,获得71.0mg标题化合物,收率93%。 [1395] 57 was prepared using the obtained 42.4mg (0.127mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butyric acid and obtained in preparation 97 40.0mg (0.126mmole) 2- pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 71.0mg of the title compound in 93% yield.

[1396] 1H NMR(CDCl3)δ9.67(1H,s),8.78-8.74(2H,m),7.50-7.41(1H,m),5.85-5.84(1H,m),5.03-4.92(1H,m),4.91-4.78(1H,m),4.27-4.22(1H,m),3.98-3.95(1H,m),3.90-3.73(3H,m),3.67-3.57(2H,m),3.21-3.09(2H,m),2.91-2.87(1H,m),2.67-2.56(3H,m),2.35-2.30(2H,m),1.45(9H,s) [1396] 1H NMR (CDCl3) δ9.67 (1H, s), 8.78-8.74 (2H, m), 7.50-7.41 (1H, m), 5.85-5.84 (1H, m), 5.03-4.92 (1H, m), 4.91-4.78 (1H, m), 4.27-4.22 (1H, m), 3.98-3.95 (1H, m), 3.90-3.73 (3H, m), 3.67-3.57 (2H, m), 3.21- 3.09 (2H, m), 2.91-2.87 (1H, m), 2.67-2.56 (3H, m), 2.35-2.30 (2H, m), 1.45 (9H, s)

[1397] 质量(m/e)599(M+1) [1397] mass (m / e) 599 (M + 1)

[1398] 实施例71:合成1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氧吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1398] Example 71: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dioxo pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1399] [1399]

[1400] 利用制备118获得的65mg(0.109mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯,以实施例22的相同方式,获得34.4mg标题化合物,收率64%。 [1400] prepared using 118 65mg (0.109mmole) {(1S) -1 obtained - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3 - [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl, in the same manner as in Example 22 to obtain 34.4mg of the title compound in 64% yield.

[1401] 1H NMR(CD3OD)δ9.78(1H,s),9.62(1H,d,8.0Hz),9.08(1H,d,4.0Hz),8.36-8.33(1H,m),5.12-5.01(2H,m),4.02-3.67(6H,m),3.62-3.51(1H,m),3.29(1H,brs),3.20-3.09(2H,m),3.03-2.95(1H,m),2.71-2.57(2H,m),2.43-2.37(2H,m) [1401] 1H NMR (CD3OD) δ9.78 (1H, s), 9.62 (1H, d, 8.0Hz), 9.08 (1H, d, 4.0Hz), 8.36-8.33 (1H, m), 5.12-5.01 ( 2H, m), 4.02-3.67 (6H, m), 3.62-3.51 (1H, m), 3.29 (1H, brs), 3.20-3.09 (2H, m), 3.03-2.95 (1H, m), 2.71- 2.57 (2H, m), 2.43-2.37 (2H, m)

[1402] 质量(m/e)499(M+1) [1402] mass (m / e) 499 (M + 1)

[1403] 制备119:合成(R)-(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐 Preparation of [1403] 119: Synthesis of (R) - (2- amino-l - methyl-ethoxy) - acetate hydrochloride

[1404] (1)合成(R)-(2-羟基-丙基)-氨基甲酸叔-丁酯 [1404] (1) Synthesis of (R) - (2- hydroxy - propyl) - carbamic acid tert - butyl ester

[1405] 除了利用500mg(R)-1-氨基-丙-2-醇(6.65mmol)之外,以制备6-(1)的相同方式,获得723mg(4.1mmol)标题化合物,收率61%。 [1405] Besides using 500mg (R) -1- amino - propan-2-ol (6.65 mmol) outside, prepared in the same manner 6- (1) to obtain 723mg (4.1mmol) of the title compound in 61% yield .

[1406] NMR:1H-NMR(CDCl3)δ4.91(1H,brs),3.95~3.85(1H,m),3.30~3.22(1H,m),3.05~2.95(1H,m),1.43(9H,s),1.16(3H,d,J=4Hz) [1406] NMR: 1H-NMR (CDCl3) δ4.91 (1H, brs), 3.95 ~ 3.85 (1H, m), 3.30 ~ 3.22 (1H, m), 3.05 ~ 2.95 (1H, m), 1.43 (9H , s), 1.16 (3H, d, J = 4Hz)

[1407] 质量(EI)176(M++1) [1407] mass (EI) 176 (M ++ 1)

[1408] (2)合成(R)-(2-叔-丁氧基羰基氨基-1-甲基-乙氧基)-乙酸乙酯 [1408] (2) Synthesis of (R) - (2- tert - butoxycarbonylamino-1-methyl - ethoxy) - ethyl

[1409] 除了利用4.93g(28.1mmol)(R)-(2-羟基-丙基)-氨基甲酸叔-丁酯(步骤1的产物)之外,以制备10-(1)的相同方式,获得4.5g(17.1mmol)标题化合物,收率60%。 [1409] In addition to 4.93g (28.1mmol) (R) using - (2-hydroxy - propyl) - carbamic acid tert - outside (product of step 1) ester, prepared 10- (1) in the same manner, to obtain 4.5g (17.1mmol) of the title compound in 60% yield.

[1410] NMR:1H-NMR(CDCl3)δ5.39(1H,s),4.23(2H,q,J=8Hz),4.09(1H,d,J=16Hz),4.00(1H,d,J=16Hz),3.60~3.35(1H,m),3.35~3.15(1H,m),3.10~3.04(1H,m),1.46(9H,s),1.31(3H,t,J=4Hz),1.16(3H,d,J=4Hz) [1410] NMR: 1H-NMR (CDCl3) δ5.39 (1H, s), 4.23 (2H, q, J = 8Hz), 4.09 (1H, d, J = 16Hz), 4.00 (1H, d, J = 16Hz), 3.60 ~ 3.35 (1H, m), 3.35 ~ 3.15 (1H, m), 3.10 ~ 3.04 (1H, m), 1.46 (9H, s), 1.31 (3H, t, J = 4Hz), 1.16 ( 3H, d, J = 4Hz)

[1411] 质量(EI)262(M++1) [1411] mass (EI) 262 (M ++ 1)

[1412] (3)合成(R)-(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐 [1412] (3) Synthesis of (R) - (2- amino-l - methyl-ethoxy) - acetate hydrochloride

[1413] 除了利用4.5g(17.1mmol)(R)-(2-叔-丁氧基羰基氨基-1-甲基-乙氧基)-乙酸乙酯(步骤1的产物)之外,以制备10-(2)的相同方式,获得2.8g(14mmol)标题化合物,收率81%。 [1413] Besides using 4.5g (17.1mmol) (R) - (2- tert - butoxycarbonylamino-1-methyl - ethoxy) - ethyl acetate (product of step 1), the prepared the same manner as 10- (2) to give 2.8g (14mmol) of the title compound in a yield of 81%.

[1414] NMR:1H-NMR(CDCl3)δ8.55(2H,s),4.25(2H,q,J=8Hz),4.22(1H,d,J=20Hz),4.03(1H,d,J=20Hz),3.80~3.70(1H,m),3.27~3.23(1H,m),3.03~2.97(1H,m),1.29(3H,t,J=4Hz),1.23(3H,d,J=4Hz) [1414] NMR: 1H-NMR (CDCl3) δ8.55 (2H, s), 4.25 (2H, q, J = 8Hz), 4.22 (1H, d, J = 20Hz), 4.03 (1H, d, J = 20Hz), 3.80 ~ 3.70 (1H, m), 3.27 ~ 3.23 (1H, m), 3.03 ~ 2.97 (1H, m), 1.29 (3H, t, J = 4Hz), 1.23 (3H, d, J = 4Hz )

[1415] 质量(EI)200(M++1) [1415] mass (EI) 200 (M ++ 1)

[1416] 制备120:合成(S)-5-氨基-4-甲基-戊酸甲酯盐酸盐 [1416] Preparation 120: Synthesis of (S) -5- amino-4-methyl - pentanoic acid methyl ester hydrochloride

[1417] (1)合成(R)-3-叠氮基-2-甲基-丙酸甲酯 [1417] (1) Synthesis of (R) -3- azido-2-methyl - propionic acid methyl ester

[1418] 利用5g(R)-3-羟基-2-甲基-丙酸甲酯(42.3mmol),以制备1-(4)的相同方式,获得(R)-3-甲磺酰氧基-2-甲基-丙酸甲酯,其无需任何进一步纯化而用于下一反应。 [1418] 5g using (R) -3- hydroxy-2-methyl - propionic acid methyl ester (42.3 mmol), prepared in the same manner as in 1- (4), to obtain (R) -3- methanesulfonyloxy -2-methyl - propionic acid methyl ester, which was used without any further purification in the next reaction.

[1419] 将(R)-3-甲磺酰氧基-2-甲基-丙酸甲酯溶解于100mL二甲基甲酰胺,然后60℃下向其中加入8.2g(126mmol)叠氮钠,接着搅拌24小时。 [1419] The (R) -3- methanesulfonyloxy-2-methyl - propionic acid methyl ester was dissolved in 100mL of dimethylformamide, and then at 60 deg.] C thereto 8.2g (126mmol) sodium azide was added, followed by stirring for 24 hours. 加入400mL乙酰乙酸乙酯并以水洗涤之后,有机层用无水硫酸镁干燥。 Was added to 400mL of ethyl acetoacetate and then washed with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到2g(13.9mmol)标题化合物,收率32%。 The solvent was distilled off, the residue was purified by column chromatography to give 2g (13.9mmol) of the title compound in a yield of 32% under reduced pressure.

[1420] 除了利用(R)-3-甲磺酰氧基-2-甲基-丙酸甲酯和5g(42.3mmol)(R)-3-羟基-2-甲基-丙酸甲酯之外,依次以制备7-(1)和制备7-(2)的相同方式,获得2g(13.9mmol)标题化合物,收率32%。 [1420] In addition to the use of (R) -3- methanesulfonyloxy-2-methyl - propionic acid methyl ester and 5g (42.3mmol) (R) -3- hydroxy-2-methyl - propionic acid methyl ester of in addition, sequentially prepared in the same manner as 7- (1) and preparation of 7- (2) to give 2g (13.9mmol) of the title compound in 32% yield.

[1421] NMR:1H-NMR(CDCl3)δ3.71(3H,s),3.54~3.52(1H,m),3.40~3.30(1H,m),2.80~2.65(1H,m),1.20(3H,d,J=7.2Hz) [1421] NMR: 1H-NMR (CDCl3) δ3.71 (3H, s), 3.54 ~ 3.52 (1H, m), 3.40 ~ 3.30 (1H, m), 2.80 ~ 2.65 (1H, m), 1.20 (3H , d, J = 7.2Hz)

[1422] 质量(EI)144(M++1) [1422] mass (EI) 144 (M ++ 1)

[1423] (2)合成(R)-3-叔-丁氧基羰基氨基-2-甲基-丙酸甲酯 [1423] (2) Synthesis of (R) -3- tert - butoxycarbonylamino-2-methyl - propionic acid methyl ester

[1424] 利用上述步骤(1)获得的2g(13.7mmol)(R)-3-叠氮基-2-甲基-丙酸甲酯,以制备7-(3)的相同方式,获得1.9g(8.7mmol)标题化合物,收率63%。 [1424] obtained by the above step (1) of 2g (13.7mmol) (R) -3- azido-2-methyl - propionic acid methyl ester, prepared in the same manner as 7- (3) to obtain 1.9g (8.7 mmol) of the title compound in 63% yield.

[1425] NMR:1H-NMR(CDCl3)δ4.92(1H,brs),3.70(3H,s),3.31~3.20(2H,m),2.70~2.55(1H,m),1.43(9H,s),1.15(3H,d,J=12Hz) [1425] NMR: 1H-NMR (CDCl3) δ4.92 (1H, brs), 3.70 (3H, s), 3.31 ~ 3.20 (2H, m), 2.70 ~ 2.55 (1H, m), 1.43 (9H, s ), 1.15 (3H, d, J = 12Hz)

[1426] 质量(EI)218(M++1) [1426] mass (EI) 218 ​​(M ++ 1)

[1427] (3)合成(R)-(3-羟基-2-甲基-丙基)-氨基甲酸叔-丁酯 [1427] (3) Synthesis of (R) - (3- hydroxy-2-methyl - propyl) - carbamic acid tert - butyl ester

[1428] 利用上述步骤(2)获得的1.9g(8.7mmol)(R)-3-叔-丁氧基羰基氨基-2-甲基-丙酸甲酯,以制备7-(4)的相同方式,获得900mg(4.7mmol)标题化合物,收率54%。 [1428] With the above steps (2) obtained 1.9g (8.7mmol) (R) -3- tert - butoxycarbonylamino-2-methyl - propionic acid methyl ester, prepared in the same 7- (4) manner, 900mg (4.7mmol) of the title compound in 54% yield.

[1429] NMR:1H-NMR(CDCl3)δ4.78(1H,brs),3.55~3.50(1H,m),3.33~3.20(2H,m),3.05~2.98(1H,m),1.75~1.65(1H,m),1.46(9H,s),0.87(3H,d,J=12Hz) [1429] NMR: 1H-NMR (CDCl3) δ4.78 (1H, brs), 3.55 ~ 3.50 (1H, m), 3.33 ~ 3.20 (2H, m), 3.05 ~ 2.98 (1H, m), 1.75 ~ 1.65 (1H, m), 1.46 (9H, s), 0.87 (3H, d, J = 12Hz)

[1430] 质量(EI)190(M++1) [1430] mass (EI) 190 (M ++ 1)

[1431] (4)合成(R)-(2-甲基-3-氧代-丙基)-氨基甲酸叔-丁酯 [1431] (4) Synthesis of (R) - (2- methyl-3-oxo - propyl) - carbamic acid tert - butyl ester

[1432] 除了利用上述步骤(3)获得的900mg(4.7mmol)(R)-(3-羟基-2-甲基-丙基)-氨基甲酸叔-丁酯之外,以制备6-(2)的相同方式,获得850mg(4.5mmol)标题化合物,收率95%。 [1432] 900mg (4.7mmol) (R) except for using the above-described step (3) obtained in - (3-methyl-2-hydroxy - propyl) - carbamic acid tert - butyl ester addition to the preparation of 6- (2 ) in the same manner to obtain 850mg (4.5mmol) of the title compound in a yield of 95%.

[1433] 质量(EI)188(M++1) [1433] mass (EI) 188 (M ++ 1)

[1434] (5)合成(S)-5-叔-丁氧基羰基氨基-4-甲基-2-戊烯酸甲酯 [1434] (5) Synthesis of (S) -5- tert - butoxycarbonylamino-4-methyl-2-pentenoate

[1435] 除了利用上述步骤(4)获得的850mg(4.5mmol)(R)-(2-甲基-3-氧代-丙基)-氨基甲酸叔-丁酯之外,以制备6-(3)的相同方式,获得1.19g(4.4mmol)标题化合物,收率97%。 [1435] 850mg (4.5mmol) (R) except for using the above-described step (4) obtained in - (2-methyl-3-oxo - propyl) - carbamic acid tert - butyl ester addition to the preparation of 6- ( 3) in the same manner to obtain 1.19g (4.4mmol) of the title compound in a yield of 97%.

[1436] NMR:1H-NMR(CDCl3)δ6.84(1H,dd,J=15Hz,10Hz),5.84(1H,d,J=15Hz),4.55(1H,brs),3.72(3H,s),3.25~3.15(1H,m),3.06~3.00(1H,m),2.54~2.47(1H,m),1.42(9H,s),1.03(3H,d,J=15Hz) [1436] NMR: 1H-NMR (CDCl3) δ6.84 (1H, dd, J = 15Hz, 10Hz), 5.84 (1H, d, J = 15Hz), 4.55 (1H, brs), 3.72 (3H, s) , 3.25 ~ 3.15 (1H, m), 3.06 ~ 3.00 (1H, m), 2.54 ~ 2.47 (1H, m), 1.42 (9H, s), 1.03 (3H, d, J = 15Hz)

[1437] 质量(EI)244(M++1) [1437] mass (EI) 244 (M ++ 1)

[1438] (6)合成(S)-5-叔-丁氧基羰基氨基-4-甲基-戊酸甲酯 [1438] (6) Synthesis of (S) -5- tert - butoxycarbonylamino-4-methyl - pentanoic acid methyl ester

[1439] 除了利用上述步骤(5)获得的1.09g(4.4mmol)(S)-5-叔-丁氧基羰基氨基-4-甲基-2-戊烯酸甲酯之外,以制备7-(7)的相同方式,获得790mg(3.2mmol),收率72%。 [1439] In addition to the above-described Step (5) 1.09g (4.4mmol) (S) -5- tert obtained - butoxycarbonylamino-4-methyl-2-pentenoate addition, to prepare 7 - (7) in the same manner to obtain 790mg (3.2mmol), 72% yield.

[1440] NMR:1H-NMR(CDCl3)δ4.90(1H,brs),3.67(3H,s),3.06~2.84(2H,m),2.43~2.27(2H,m),1.75~1.58(2H,m),1.48~1.44(1H,m),1.44(9H,s),0.88(3H,d,J=6.8Hz) [1440] NMR: 1H-NMR (CDCl3) δ4.90 (1H, brs), 3.67 (3H, s), 3.06 ~ 2.84 (2H, m), 2.43 ~ 2.27 (2H, m), 1.75 ~ 1.58 (2H , m), 1.48 ~ 1.44 (1H, m), 1.44 (9H, s), 0.88 (3H, d, J = 6.8Hz)

[1441] 质量(EI)246(M++1) [1441] mass (EI) 246 (M ++ 1)

[1442] (7)合成(S)-5-氨基-4-甲基-戊酸甲酯盐酸盐 [1442] (7) Synthesis of (S) -5- amino-4-methyl - pentanoic acid methyl ester hydrochloride

[1443] 除了利用上述步骤(6)获得的790mg(3.2mmol)(S)-5-叔-丁氧基羰基氨基-4-甲基-戊酸甲酯之外,以制备1-(4)的相同方式,获得570mg(3.1mmol)标题化合物,收率96%。 [1443] 790mg (3.2mmol) (S) -5- tert except for using the above-described step (6) obtained in - butoxycarbonylamino-4-methyl - outside pentanoic acid methyl ester, was prepared 1- (4) in the same manner to obtain 570mg (3.1mmol) of the title compound in a yield of 96%.

[1444] NMR:1H-NMR(CD3OD)δ3.69(3H,s),2.94~2.89(1H,m),2.79~2.74(1H,m),2.52~2.36(2H,m),1.86~1.74(2H,m),1.54~1.47(1H,m),1.04(3H,d,J=7.2Hz) [1444] NMR: 1H-NMR (CD3OD) δ3.69 (3H, s), 2.94 ~ 2.89 (1H, m), 2.79 ~ 2.74 (1H, m), 2.52 ~ 2.36 (2H, m), 1.86 ~ 1.74 (2H, m), 1.54 ~ 1.47 (1H, m), 1.04 (3H, d, J = 7.2Hz)

[1445] 质量(EI)182(M++1) [1445] mass (EI) 182 (M ++ 1)

[1446] 制备121:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5S)-5-甲基-2-氧代哌啶-1-基]-丁酸叔-丁酯 [1446] Preparation 121: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5S) -5- methyl-2-oxo-piperidin-1-yl] - butoxy acid tert - butyl ester

[1447] 除了利用3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯(制备41的产物)和700mg(3.85mmol)(S)-5-氨基-4-甲基-戊酸甲酯盐酸盐(制备120的产物)之外,以制备42的相同方式,获得770mg标题化合物,收率54%。 [1447] In addition to using 3S- tert - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester (the product of Preparation 41) and 700mg (3.85mmol) (S) -5- amino-4- - addition pentanoate hydrochloride (the product of preparation 120), in the same manner as in preparation 42, to obtain 770mg of the title compound in 54% yield.

[1448] 1H NMR(CDCl3)δ5-37(1H,d,J=7.0Hz),4.1-4.2(1H,m),3.8-3.9(1H,m),3.4-3.5(1H,m),3.0-3.1(1H,m),2.9(1H,m),2.3-2.6(4H,m),1.8-2.0(2H,m),1.45(9H,s),1.41(9H,s),1.0(3H,d,J=7.0Hz) [1448] 1H NMR (CDCl3) δ5-37 (1H, d, J = 7.0Hz), 4.1-4.2 (1H, m), 3.8-3.9 (1H, m), 3.4-3.5 (1H, m), 3.0 -3.1 (1H, m), 2.9 (1H, m), 2.3-2.6 (4H, m), 1.8-2.0 (2H, m), 1.45 (9H, s), 1.41 (9H, s), 1.0 (3H , d, J = 7.0Hz)

[1449] 质量(m/e)371(M+1) [1449] mass (m / e) 371 (M + 1)

[1450] 制备122:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5S)-5-甲基-2-氧代哌啶-1-基]-丁酸 [1450] Preparation 122: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5S) -5- methyl-2-oxo-piperidin-1-yl] - butoxy acid

[1451] 除了利用770mg(0.97mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5S)-5-甲基-2-氧代哌啶-1-基]-丁酸叔-丁酯(制备121的产物)之外,以制备43的相同方式,获得528mg标题化合物,总收率81%。 [1451] Besides using 770mg (0.97mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5S) -5- methyl-2-oxo-piperidin-1-yl ] - butyric acid tert - butyl outside (the product of preparation 121), in the same manner as in preparation 43 to give the title compound 528mg, 81% overall yield.

[1452] 1H NMR(CDCl3)δ5.6(1H,m),3.4-3.7(3H,m),3.0-3.1(2H,m),2.3-2.6(4H,m),1.8-2.0(2H,m),1.41(9H,s),1.01(3H,d,J=6.5Hz) [1452] 1H NMR (CDCl3) δ5.6 (1H, m), 3.4-3.7 (3H, m), 3.0-3.1 (2H, m), 2.3-2.6 (4H, m), 1.8-2.0 (2H, m), 1.41 (9H, s), 1.01 (3H, d, J = 6.5Hz)

[1453] 质量(m/e)315(M+1) [1453] mass (m / e) 315 (M + 1)

[1454] 制备123:合成[(2-氨基-1-甲基乙基)硫代]乙酸甲酯 [1454] Preparation 123: Synthesis of [(2-amino-1-methylethyl) thio] acetate

[1455] (1)合成3-[(2-甲氧基-2-氧代乙基)硫代]丁酸叔-丁酯 [1455] (1) Synthesis of 3 - [(2-methoxy-2-oxoethyl) thio] butanoic acid tert - butyl ester

[1456] 将硫基乙醇酸甲酯(0.8mL,8.9mmol)、哌啶(0.12mL,1.2mmol)和2g(14mmol)巴豆酸叔-丁酯的混合物室温下搅拌12小时,接着减压下蒸馏。 The mixture was stirred for 12 hours at room temperature butyl, then under reduced pressure - t crotonic acid [1456] The methyl thioglycolate (0.8mL, 8.9mmol), piperidine (0.12mL, 1.2mmol) and 2g (14mmol) distillation. 反应液通过柱层析纯化,得到2.05g(8.2mmol)标题化合物,收率92%。 The reaction solution was purified by column chromatography to give 2.05g (8.2mmol) of the title compound in 92% yield.

[1457] NMR:1H-NMR(CDCl3)δ3.74(3H,s),3.34~3.25(2H,m),2.57(1H,dd,J=6.0Hz,15.2Hz),2.37(1H,dd,J=8.4Hz,15.6Hz),1.84(1H,dd,J=2Hz,7.2Hz),1.45(9H,s),1.34(3H,d,J=6.8Hz) [1457] NMR: 1H-NMR (CDCl3) δ3.74 (3H, s), 3.34 ~ 3.25 (2H, m), 2.57 (1H, dd, J = 6.0Hz, 15.2Hz), 2.37 (1H, dd, J = 8.4Hz, 15.6Hz), 1.84 (1H, dd, J = 2Hz, 7.2Hz), 1.45 (9H, s), 1.34 (3H, d, J = 6.8Hz)

[1458] 质量(EI)249(M++1) [1458] mass (EI) 249 (M ++ 1)

[1459] (2)合成3-[(2-甲氧基-2-氧代乙基)硫代]丁酸 [1459] (2) Synthesis of 3 - [(2-methoxy-2-oxoethyl) thio] butanoic acid

[1460] 将1.5g(6.0mmol)3-[(2-甲氧基-2-氧代乙基)硫代]丁酸叔-丁酯(步骤1的产物)与10mL二氯甲烷和5mL三氟乙酸室温下一起搅拌6小时,接着减压下蒸馏。 [1460] A 1.5g (6.0mmol) 3 - [(2- methoxy-2-oxoethyl) thio] butanoic acid tert - butyl ester (product of step 1) with three 5mL and 10mL dichloromethane fluoro stirred for 6 hours at room temperature with acetic acid, and then distilled under reduced pressure. 加入40mL乙酰乙酸乙酯并以水洗涤之后,有机层用无水硫酸镁干燥。 Was added to 40mL of ethyl acetoacetate and then washed with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂,残留物通过柱层析纯化,得到1g(5.1mmol)标题化合物,收率85%。 The solvent was distilled off, the residue was purified by column chromatography to give 1g (5.1mmol) of the title compound in a yield of 85% under reduced pressure.

[1461] NMR:1H-NMR(CDCl3)δ3.75(3H,s),3.39~3.27(3H,m),2.73(1H,dd,J=6.4Hz,16Hz),2.55(1H,dd,J=7.6Hz,16Hz),1.39(3H,d,J=6.8Hz) [1461] NMR: 1H-NMR (CDCl3) δ3.75 (3H, s), 3.39 ~ 3.27 (3H, m), 2.73 (1H, dd, J = 6.4Hz, 16Hz), 2.55 (1H, dd, J = 7.6Hz, 16Hz), 1.39 (3H, d, J = 6.8Hz)

[1462] 质量(EI)193(M++1) [1462] mass (EI) 193 (M ++ 1)

[1463] (3)合成[(2-氨基-1-甲基乙基)硫代]乙酸甲酯 [1463] (3) Synthesis of [(2-amino-1-methylethyl) thio] acetate

[1464] 将300mg(1.56mmol)3-[(2-甲氧基-2-氧代乙基)硫代]丁酸(步骤2的产物)溶解于12mL四氢呋喃,然后向其中滴加0.55mL(3.93mmol)三乙胺。 [1464] A 300mg (1.56mmol) 3 - [(2- methoxy-2-oxoethyl) thio] butanoic acid (product of step 2) was dissolved in 12mL of tetrahydrofuran, was then added dropwise 0.55 mL ( 3.93mmol) of triethylamine. 0℃下滴加0.4mL(3.08mmol)氯甲酸异丁酯。 Was added dropwise 0.4mL (3.08mmol) isobutyl chloroformate at 0 ℃. 搅拌1小时后,将1.8g(27.6mmol)叠氮钠溶解于6mL水形成的溶液倾入所得混合物中,然后反应进行30分钟。 After stirring for 1 hour, 1.8g (27.6mmol) of sodium azide were dissolved in water to form a solution 6mL poured into the resulting mixture, followed by reaction for 30 minutes. 加入50mL乙酰乙酸乙酯并以水洗涤之后,有机层用无水硫酸镁干燥。 Was added to 50mL of ethyl acetoacetate and then washed with water, the organic layer was dried over anhydrous magnesium sulfate. 减压下蒸馏掉溶剂后,所得溶液无需任何进一步纯化就可使用。 After the solvent was distilled off under reduced pressure, and the resulting solution was used without any further purification.

[1465] 将上述溶液溶解于5mL苯,然后向其中加入三乙胺(0.45mL,3.2mmol)和4-甲氧基苄醇(0.39mL,3.12mmol),接着80℃下搅拌1小时。 [1465] The above solution was dissolved in 5mL of benzene, and thereto was added triethylamine (0.45mL, 3.2mmol) and 4-methoxybenzyl alcohol (0.39 mL, 3.12 mmol), followed by stirring at 80 ℃ 1 hour. 减压下蒸馏掉溶剂,然后残留物通过柱层析纯化,得到[(2-(4-甲氧基苄基氨基)-1-甲基乙基)硫代]乙酸甲酯。 The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give [(2- (4-methoxy-benzylamino) -1-methylethyl) thio] acetate.

[1466] 上述化合物与4mL二氯甲烷和2mL三氟乙酸一起室温下搅拌3小时。 [1466] The mixture was stirred for 3 hours at room temperature together with 4mL of dichloromethane and 2mL of trifluoroacetic acid. 减压下蒸发掉溶剂,然后残留物通过柱层析纯化,得到250mg(1.4mmol)标题化合物,收率89%。 The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give 250mg (1.4mmol) of the title compound in 89% yield.

[1467] NMR:1H-NMR(CDCl3)δ8.05(2H,s),3.76(3H,s),3.45~3.30(2H,m),3.27~3.20(1H,m),3.15~3.05(1H,m),2.90~2.78(1H,m),1.40(3H,d,J=6.4Hz) [1467] NMR: 1H-NMR (CDCl3) δ8.05 (2H, s), 3.76 (3H, s), 3.45 ~ 3.30 (2H, m), 3.27 ~ 3.20 (1H, m), 3.15 ~ 3.05 (1H , m), 2.90 ~ 2.78 (1H, m), 1.40 (3H, d, J = 6.4Hz)

[1468] 质量(EI)164(M++1) [1468] mass (EI) 164 (M ++ 1)

[1469] 制备124:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(2-甲基-5-氧代硫代吗啉-4-基)-丁酸叔-丁酯 [1469] Preparation 124: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (2-methyl-5-oxo-thiomorpholin-4-yl) - butanoic acid tert - butyl

[1470] 除了利用3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯(制备41的产物)和制备123获得的200mg(0.72mmol)[(2-氨基-1-甲基乙基)硫代]乙酸甲酯之外,以制备42的相同方式,获得210mg标题化合物,收率75%。 [1470] In addition to using 3S- tert - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester 200 mg of (the product of Preparation 41) was prepared and obtained in 123 (0.72mmol) [(2- amino-1- methylethyl) outside thio] acetate, prepared in the same manner as 42, to obtain 210mg of the title compound in 75% yield.

[1471] 1H NMR(CDCl3)δ5.21(1H,m),3.9-4.0(1H,m),3.7-3.8(3H,m),3.2-3.3(3H,m),2.5-2.6(2H,m),2.3-2.4(1H,m),1.44(9H,s),1.43(9H,s),1.2-1.3(3H,m) [1471] 1H NMR (CDCl3) δ5.21 (1H, m), 3.9-4.0 (1H, m), 3.7-3.8 (3H, m), 3.2-3.3 (3H, m), 2.5-2.6 (2H, m), 2.3-2.4 (1H, m), 1.44 (9H, s), 1.43 (9H, s), 1.2-1.3 (3H, m)

[1472] 质量(m/e)389(M+1) [1472] mass (m / e) 389 (M + 1)

[1473] 制备125:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(2-甲基-5-氧代硫代吗啉-4-基)-丁酸 [1473] Preparation 125: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (2-methyl-5-oxo-thiomorpholin-4-yl) - butanoic acid

[1474] 除了利用制备124获得的210mg(0.54mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(2-甲基-5-氧代硫代吗啉-4-基)-丁酸叔-丁酯之外,以制备43的相同方式,获得50mg标题化合物,总收率28%。 [1474] Preparation 124 except for using the obtained 210mg (0.54mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (2-methyl-5-oxo-thiomorpholine-4 - yl) - butanoic acid tert - butyl ester addition, in the same manner as in preparation 43 to give the title compound 50mg, 28% overall yield.

[1475] 1H NMR(CDCl3)δ5.61(1H,br s),3.5-3.8(4H,m),3.2-3.4(3H,m),2.5-2.7(3H,m),1.41(9H,s),1.29(3H,d,J=7.0Hz) [1475] 1H NMR (CDCl3) δ5.61 (1H, br s), 3.5-3.8 (4H, m), 3.2-3.4 (3H, m), 2.5-2.7 (3H, m), 1.41 (9H, s ), 1.29 (3H, d, J = 7.0Hz)

[1476] 质量(m/e)233(M-tBoc) [1476] mass (m / e) 233 (M-tBoc)

[1477] 制备126:合成2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1477] Preparation 126: Synthesis of 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1478] (1)合成2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1478] (1) Synthesis of 2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1479] 将1.3mL甲醇钠(21%wt.乙醇溶液)室温下添加至283mg(3.0mmol)乙脒盐酸盐溶解于5mL无水乙醇形成的溶液。 [1479] A 1.3mL of sodium methoxide (21% wt. Ethanol solution) was added to 283mg (3.0mmol) acetamidine hydrochloride was dissolved in 5mL of absolute ethanol at room temperature was formed. 搅拌15分钟之后,向所得溶液加入用5mL无水乙醇稀释的制备47获得的590mg(2.0mmol)3-氧代-4-(三氟乙酰)-哌啶-1-羧酸叔-丁酯的溶液。 After stirring for 15 minutes, the resulting solution was added 590mg (2.0mmol) 3- oxo prepared 5mL diluted with absolute ethanol to obtain 47-4- (trifluoroacetyl) - piperidine-1-carboxylic acid tert - butyl ester solution. 所得混合物加热至80℃,搅拌18小时。 The resulting mixture was heated to 80 ℃, stirred for 18 hours. 冷却至室温后,减压下蒸馏掉乙醇,接着用乙酸乙酯稀释的盐水洗涤。 After cooling to room temperature, ethanol was distilled off under reduced pressure, then diluted with ethyl acetate and washed with brine. 有机层用无水硫酸镁干燥,减压下蒸馏掉溶剂,然后残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到98mg标题化合物,收率16%。 The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (10:1 hexanes: ethyl acetate) to give the title compound 98mg, 16% yield.

[1480] 1H NMR(CDCl3)δ4.70(2H,s),3.72(2H,t,J=8.0Hz),3.00(2H,brs),1.50(9H,s) [1480] 1H NMR (CDCl3) δ4.70 (2H, s), 3.72 (2H, t, J = 8.0Hz), 3.00 (2H, brs), 1.50 (9H, s)

[1481] 质量(m/e)318(M+1) [1481] mass (m / e) 318 (M + 1)

[1482] (2)合成2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1482] (2) Synthesis of 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1483] 利用上述步骤(1)获得的98mg(0.306mmol)2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯,以制备49的相同方式,获得70mg标题化合物,收率90%。 [1483] obtained by the above step (1) of 98mg (0.306mmol) 2- methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - carboxylic acid tert - butyl ester, 49 was prepared in the same manner to obtain 70mg of the title compound in 90% yield.

[1484] 1H NMR(CD3OD)δ4.45(2H,s),3.59(2H,t,J=7.0Hz),3.29(2H,m),2.72(3H,s) [1484] 1H NMR (CD3OD) δ4.45 (2H, s), 3.59 (2H, t, J = 7.0Hz), 3.29 (2H, m), 2.72 (3H, s)

[1485] 质量(m/e)218(M+1) [1485] mass (m / e) 218 ​​(M + 1)

[1486] 制备127:合成2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1486] Preparation 127: Synthesis of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1487] (1)合成2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1487] (1) Synthesis of 2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1488] 将制备47获得的800mg(2.71mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和455mg(4.06mmol)三氟乙脒一起在25mL乙醇搅拌15小时,同时加热至90℃。 [1488] The preparation 47 800mg (2.71mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained tert - butyl ester and 455mg (4.06mmol) along with trifluoroacetamidine in 25mL ethanol stirred for 15 hours while heating to 90 ℃. 冷却至室温之后,去除乙醇,之后所得溶液用乙酸乙酯稀释,接着用盐水洗涤。 After cooling to room temperature, ethanol was removed, then the resulting solution was diluted with ethyl acetate, followed by brine. 有机层用无水硫酸镁干燥,减压下蒸馏掉溶剂,残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到230mg标题化合物,收率23%。 The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (10:1 hexanes: ethyl acetate) to give 230mg of the title compound in 23% yield.

[1489] 1H NMR(CDCl3)δ4.67(2H,s),3.72(2H,t,J=8.0Hz),3.12(2H,brs),1.52(9H,s) [1489] 1H NMR (CDCl3) δ4.67 (2H, s), 3.72 (2H, t, J = 8.0Hz), 3.12 (2H, brs), 1.52 (9H, s)

[1490] 质量(m/e)372(M+1) [1490] mass (m / e) 372 (M + 1)

[1491] (2)合成2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1491] (2) Synthesis of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1492] 除了利用上述步骤(1)获得的230mg(0.62mmol)2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备49的相同方式,获得184mg标题化合物,收率96%。 [1492] 230mg except for using the above-described step (1) obtained in (0.62 mmol) 2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as in preparation 49, to obtain 184mg of the title compound in 96% yield.

[1493] 1H NMR(CD3OD)δ4.66(2H,s),3.69(2H,t,J=7.5Hz),3.42(2H,t,J=7.5Hz) [1493] 1H NMR (CD3OD) δ4.66 (2H, s), 3.69 (2H, t, J = 7.5Hz), 3.42 (2H, t, J = 7.5Hz)

[1494] 质量(m/e)272(M+1) [1494] mass (m / e) 272 (M + 1)

[1495] 制备128:合成2-乙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1495] Preparation 128: Synthesis of 2-ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1496] (1)合成丙烷酰亚胺酰胺(propaneimidamide) [1496] (1) Synthesis of propane-carboximidamide (propaneimidamide)

[1497] 将9.07mL(18.14mmol)三甲基铝(2.0M甲苯溶液)室温下滴加至40mL含有971mg(18.1mmol)氯化铵的甲苯中。 [1497] A solution of 9.07mL (18.14mmol) of trimethylaluminum (2.0M solution in toluene) at room temperature to 40mL of toluene containing 971mg (18.1mmol) of ammonium chloride. 搅拌1.5小时之后,向其中加入1g(18.1mmol)丙腈,接着加热至85℃,9小时。 After stirring for 1.5 hours, and thereto was added 1g (18.1mmol) propionitrile, followed by heating to 85 ℃, 9 hours. 反应完成后,所得溶液冷却,然后倾入100mL含有200g硅胶的氯仿,接着过滤。 After completion of the reaction, the resulting solution was cooled, then poured into 100mL of chloroform containing 200g of silica gel, followed by filtration. 残留物以100mL甲醇洗涤,然后进行蒸馏,得到1.01g(14mmol)标题化合物,收率77%。 The residue was washed with 100mL methanol and then distilled to obtain 1.01g (14mmol) of the title compound in 77% yield.

[1498] NMR:1H-NMR(CD3OD)δ2.46~2.44(2H,m),1.28~1.24(3H,m)质量(EI)73(M++1) [1498] NMR: 1H-NMR (CD3OD) δ2.46 ~ 2.44 (2H, m), 1.28 ~ 1.24 (3H, m) mass (EI) 73 (M ++ 1)

[1499] (2)合成2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1499] (2) Synthesis of 2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1500] 除了利用制备47获得的1.6g(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的508mg(7.04mmol)丙烷酰亚胺酰胺之外,以制备48的相同方式,获得160mg标题化合物,收率9%。 [1500] In addition to using Preparation 47 1.6g (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained - 508mg (7.04mmol butyl and the above step (1) obtained in addition) propane polyimide amide, in the same manner as in preparation 48 to give the title compound 160mg, 9% yield.

[1501] 1H NMR(CDCl3)δ4.70(2H,s),3.72(2H,t,J=7.0Hz),3.0(2H,m),3.0(2H,q,J=7.5Hz),1.50(9H,s),1.37(3H,t,J=7.5Hz) [1501] 1H NMR (CDCl3) δ4.70 (2H, s), 3.72 (2H, t, J = 7.0Hz), 3.0 (2H, m), 3.0 (2H, q, J = 7.5Hz), 1.50 ( 9H, s), 1.37 (3H, t, J = 7.5Hz)

[1502] 质量(m/e)332(M+1) [1502] mass (m / e) 332 (M + 1)

[1503] (3)合成2-乙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1503] (3) Synthesis of 2-ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1504] 除了利用上述步骤(2)获得的160mg(0.62mmol)2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备49的相同方式,获得60mg标题化合物,收率54%。 [1504] 160mg except for using the above-described step (2) obtained in (0.62mmol) 2- ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - carboxylic acid tert - butyl ester addition, in the same manner as in preparation 49, to obtain 60mg of the title compound in 54% yield.

[1505] 1H NMR(CD3OD)δ4.29(2H,s),3.42(2H,t,J=7.0Hz),3.12(2H,br s),2.98(2H,q,J=7.5Hz),1.32(3H,t,J=7.5Hz) [1505] 1H NMR (CD3OD) δ4.29 (2H, s), 3.42 (2H, t, J = 7.0Hz), 3.12 (2H, br s), 2.98 (2H, q, J = 7.5Hz), 1.32 (3H, t, J = 7.5Hz)

[1506] 质量(m/e)232(M+1) [1506] mass (m / e) 232 (M + 1)

[1507] 制备129:合成2-(五氟乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1507] Preparation 129: Synthesis of 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1508] (1)合成2-(五氟乙基)-4-(三氟甲基)-5,9-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1508] (1) Synthesis of 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,9-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1509] 将制备47获得的820mg(2.78mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和585mg(3.61mmol)of 2,2,3,3,3-五氟丙烷酰亚胺酰胺添加到50mL异丙醇,再滴加10l BF3OEt2(3%:催化量),所得混合物加热至120℃,并搅拌17小时。 [1509] The preparation 47 820mg (2.78mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained - butyl ester and 585mg (3.61mmol) of 2,2,3,3 , 3-pentafluoropropane was added to the polyimide amide 50mL of isopropanol was added dropwise 10l BF3OEt2 (3%: catalyst amount), and the resulting mixture was heated to 120 deg.] C, and stirred for 17 hours. 室温下添加1~2滴饱和碳酸氢钠,接着冷却至室温。 Add two drops of saturated sodium bicarbonate at room temperature, then cooled to room temperature. 减压下蒸馏掉异丙醇,残留物通过柱层析纯化(10∶1己烷∶乙酸乙酯),得到690mg标题化合物,收率59%。 (: Ethyl acetate 10 hexane) to give 690mg of the title compound, yield 59% isopropanol was distilled off the residue was purified by column chromatography under reduced pressure.

[1510] 1H NMR(CDCl3)δ4.84(2H,s),3.77(2H,t,J=5.5Hz),3.11(2H,brs),1.50(9H,s) [1510] 1H NMR (CDCl3) δ4.84 (2H, s), 3.77 (2H, t, J = 5.5Hz), 3.11 (2H, brs), 1.50 (9H, s)

[1511] 质量(m/e)422(M+1) [1511] mass (m / e) 422 (M + 1)

[1512] (2)合成2-(五氟乙基)-4-(三氟甲基)-5,6,7,8-甲氢吡啶并[3,4-d]嘧啶盐酸盐 [1512] (2) Synthesis of 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-methyl hydrogen pyrido [3,4-d] pyrimidine hydrochloride

[1513] 除了利用上述步骤(1)获得的690mg(0.08mmol)叔-丁基-2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯之外,以制备49的相同方式,获得506mg标题化合物,收率96%。 [1513] In addition to the above steps (1) obtained 690mg (0.08mmol) tert - butyl-2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - carboxylate outside, in the same manner as in preparation 49, to obtain 506mg of the title compound in 96% yield.

[1514] 1H NMR(CD3OD)δ4.65(2H,s),3.66(2H,t,J=6.0Hz),3.40(2H,m) [1514] 1H NMR (CD3OD) δ4.65 (2H, s), 3.66 (2H, t, J = 6.0Hz), 3.40 (2H, m)

[1515] 质量(m/e)322(M+1) [1515] mass (m / e) 322 (M + 1)

[1516] 制备130:合成2-异丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1516] Preparation 130: Synthesis of 2-isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1517] (1)合成2-甲基丙烷酰亚胺酰胺 [1517] (1) Synthesis of 2-methylpropane polyimideamide

[1518] 将14.5mL(29mmol)三甲基铝(2.0M甲苯溶液)室温下滴加至20mL含有1.55g(28.9mmol)氯化铵的甲苯中。 [1518] A solution of 14.5mL (29mmol) of trimethylaluminum (2.0M solution in toluene) at room temperature to 20mL of toluene containing 1.55g of ammonium chloride (28.9mmol). 搅拌1.5小时后,向其中添加2g(28.9mmol)异丁腈(isobutironitrile),所得混合物加热至85℃,9小时。 After stirring for 1.5 hours, and thereto was added 2g (28.9mmol) isobutyronitrile (isobutironitrile), the resulting mixture was heated to 85 ℃, 9 hours. 反应完成后,反应液倾入200mL含有500g硅胶的氯仿,过滤。 After completion of the reaction, the reaction solution was poured into 200mL of chloroform containing 500g of silica gel, and filtered. 残留物以200mL甲醇洗涤,蒸馏得到2.3g(26.7mmol)标题化合物,收率92%。 The residue was washed with 200mL of methanol was distilled to give 2.3g (26.7mmol) of the title compound in 92% yield.

[1519] 质量(EI)87(M++1) [1519] mass (EI) 87 (M ++ 1)

[1520] (2)合成2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1520] (2) Synthesis of 2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1521] 除了利用制备47获得的900mg(3.05mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的394mg(4.58mmo])2-甲基丙烷酰亚胺酰胺之外,以制备61的相同方式,获得174mg标题化合物,收率17%。 [1521] Besides using 900mg (3.05mmol) 3- oxo-47 obtained in Preparation 4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 394mg (4.58mmo] butyl, and the above step (1) obtained in ) of 2-methylpropane polyimide amide addition, in the same manner as in preparation 61, to obtain 174mg of the title compound in 17% yield.

[1522] 1H NMR(CDCl3)δ4.68(2H,s),3.70(2H,t,J=5.5Hz),3.21(1H,m),2.96(2H,m),1.50(9H,s),1.33(6H,d,J=7.0Hz), [1522] 1H NMR (CDCl3) δ4.68 (2H, s), 3.70 (2H, t, J = 5.5Hz), 3.21 (1H, m), 2.96 (2H, m), 1.50 (9H, s), 1.33 (6H, d, J = 7.0Hz),

[1523] 质量(m/e)346(M+1) [1523] mass (m / e) 346 (M + 1)

[1524] (3)合成 2-异丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1524] (3) Synthesis of 2-isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1525] 除了利用上述步骤(2)获得的174mg(0.5mmol)2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备49的相同方式,获得80mg标题化合物,收率56%。 [1525] In addition to the above steps (2) 174mg (0.5mmol) of 2- isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as in preparation 49 to give the title compound 80mg, 56% yield.

[1526] 1H NMR(CD3OD)δ4.71(2H,s),3.59(2H,t,J=6.0Hz),3.22(3H,m),1.33(6H,d,J=7.0Hz) [1526] 1H NMR (CD3OD) δ4.71 (2H, s), 3.59 (2H, t, J = 6.0Hz), 3.22 (3H, m), 1.33 (6H, d, J = 7.0Hz)

[1527] 质量(m/e)246(M+1) [1527] mass (m / e) 246 (M + 1)

[1528] 制备131:合成2-叔-丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1528] Preparation 131: Synthesis of 2-tert - butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1529] (1)合成2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1529] (1) Synthesis of 2-tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1530] 除了利用制备47获得的700mg(2.37mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和356mg(3.56mmol)2,2-二甲基丙烷酰亚胺酰胺之外,以制备48的相同方式,获得29mg标题化合物,收率3.4%。 [1530] Preparation 47 except using the obtained 700mg (2.37mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester and 356mg (3.56mmol) 2,2- dimethyl propane amide imide addition, in the same manner as in preparation 48, to obtain 29mg of the title compound in a yield of 3.4%.

[1531] 1H NMR(CDCl3)δ4.67(2H,s),3.71(2H,t,J=6.0Hz),2.96(2H,m),1.51(9H,s),1.39(9H,s), [1531] 1H NMR (CDCl3) δ4.67 (2H, s), 3.71 (2H, t, J = 6.0Hz), 2.96 (2H, m), 1.51 (9H, s), 1.39 (9H, s),

[1532] 质量(m/e)360(M+1) [1532] mass (m / e) 360 (M + 1)

[1533] (2)合成2-叔-丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1533] (2) Synthesis of 2-tert - butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1534] 除了利用上述步骤(1)获得的29mg(0.08mmol)2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备49的相同方式,获得18mg标题化合物,收率90%。 [1534] In addition to the above steps (1) obtained 29mg (0.08mmol) 2- tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as in preparation 49, to obtain 18mg of the title compound in 90% yield.

[1535] 1H NMR(CD3OD)δ4.45(2H,s),3.56(2H,t,J=6.0Hz),3.22(2H,brt,J=6.0Hz),1.39(9H,s) [1535] 1H NMR (CD3OD) δ4.45 (2H, s), 3.56 (2H, t, J = 6.0Hz), 3.22 (2H, brt, J = 6.0Hz), 1.39 (9H, s)

[1536] 质量(m/e)260(M+1) [1536] mass (m / e) 260 (M + 1)

[1537] 制备132:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1537] Preparation 132: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2-ethyl-4- (C fluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1538] 除了利用制备57获得的16mg(0.047mmol)(3S)-3-[(叔-丁氧羧基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备128获得的12mg(0.046mmol)2-乙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得21mg(0.038mmol)标题化合物,收率82%。 [1538] Preparation 57 except for using the obtained 16mg (0.047mmol) (3S) -3 - [(tert - butoxy carboxy) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 yl) butyric acid and prepared 128 12mg (0.046mmol) 2- ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido obtained [3,4-d] pyrimidine hydrochloride addition salt thereof, in the same manner as in preparation 45 to give 21mg (0.038mmol) of the title compound in 82% yield.

[1539] NMR:1H-NMR(CDCl3)δ5.79~5.77(1H,brs),4.89~4.78(1H,m),4.73~4.64(1H,m),4.25~4.15(1H,m),3.90~3.80(1H,m),3.74~3.71(3H,m),3,60~3.52(2H,m),3.05~2.97(4H,m),2.85~2.79(1H,m),2.60~2.50(3H,m),2.32~2.20(2H,m),1.41(9H,s),1.38~1.34(3H,m)质量(EI)550(M++1) [1539] NMR: 1H-NMR (CDCl3) δ5.79 ~ 5.77 (1H, brs), 4.89 ~ 4.78 (1H, m), 4.73 ~ 4.64 (1H, m), 4.25 ~ 4.15 (1H, m), 3.90 ~ 3.80 (1H, m), 3.74 ~ 3.71 (3H, m), 3,60 ~ 3.52 (2H, m), 3.05 ~ 2.97 (4H, m), 2.85 ~ 2.79 (1H, m), 2.60 ~ 2.50 ( 3H, m), 2.32 ~ 2.20 (2H, m), 1.41 (9H, s), 1.38 ~ 1.34 (3H, m) mass (EI) 550 (m ++ 1)

[1540] 实施例72:合成1-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮盐酸盐 [1540] Example 72: Synthesis of 1 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one hydrochloride

[1541] [1541]

[1542] 除了利用制备132获得的21mg(0.038mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得13mg(0.026mmol)标题化合物,收率68%。 [1542] In addition to 132 prepared using the obtained 21mg (0.038mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 13mg (0.026mmol) of the title compound in 68% yield.

[1543] NMR:1H-NMR(CD3OD)δ4.73~4.68(2H,m),3.80~3.67(4H,m),3.56~3.53(2H,m),3.38~3.36(1H,m),3.00~2.97(1H,m),2.91~2.85(3H,m),2.69~2.45(4H,m),2.27~2.22(2H,m),1.27~1.13(3H,m) [1543] NMR: 1H-NMR (CD3OD) δ4.73 ~ 4.68 (2H, m), 3.80 ~ 3.67 (4H, m), 3.56 ~ 3.53 (2H, m), 3.38 ~ 3.36 (1H, m), 3.00 ~ 2.97 (1H, m), 2.91 ~ 2.85 (3H, m), 2.69 ~ 2.45 (4H, m), 2.27 ~ 2.22 (2H, m), 1.27 ~ 1.13 (3H, m)

[1544] 质量(EI)450(M++1) [1544] mass (EI) 450 (M ++ 1)

[1545] 制备133:合成(1S)-(3-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基)氨基甲酸叔-丁酯 [1545] Preparation 133: Synthesis of (1S) - (3- [2- ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl) carbamic acid tert - butyl ester

[1546] 除了利用制备55获得的15mg(0.047mmol)3S-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]丁酸和12mg(0.046mmol)2-乙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备128的产物)之外,以制备45的相同方式,获得13mg(0.024mmol)标题化合物,收率51%。 [1546] Preparation 55 except for using the obtained 15mg (0.047mmol) 3S-3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-morpholin-4- - yl] butanoic acid and 12mg (0.046mmol) 2- ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride (prepared addition product 128), in the same manner as in preparation 45 to give 13mg (0.024mmol) of the title compound in 51% yield.

[1547] NMR:1H-NMR(CDCl3)δ5.82~5.77(1H,brs),4.90~4.78(1H,m),4.75~4.64(1H,m),4.24~4.09(3H,m),3.93~3.83(2H,m),3.76~3.74(1H,m),3,69~3.62(1H,m),3.53~3.47(1H,m),3.37~3.30(2H,m),3.03~2.97(4H,m),2.88~2.81(1H,m),2.59~2.49(1H,m),1.41(9H,s),1.38~1.34(3H,m),1.27~1.24(3H,m) [1547] NMR: 1H-NMR (CDCl3) δ5.82 ~ 5.77 (1H, brs), 4.90 ~ 4.78 (1H, m), 4.75 ~ 4.64 (1H, m), 4.24 ~ 4.09 (3H, m), 3.93 ~ 3.83 (2H, m), 3.76 ~ 3.74 (1H, m), 3,69 ~ 3.62 (1H, m), 3.53 ~ 3.47 (1H, m), 3.37 ~ 3.30 (2H, m), 3.03 ~ 2.97 ( 4H, m), 2.88 ~ 2.81 (1H, m), 2.59 ~ 2.49 (1H, m), 1.41 (9H, s), 1.38 ~ 1.34 (3H, m), 1.27 ~ 1.24 (3H, m)

[1548] 质量(EI)530(M++1) [1548] mass (EI) 530 (M ++ 1)

[1549] 实施例73:合成(6S)-4-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮盐酸盐 [1549] Example 73: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one hydrochloride

[1550] [1550]

[1551] 除了利用制备133获得的13mg(0.024mmol)(1S)-(3-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基)氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得9mg(0.019mmol)标题化合物,收率79%。 [1551] Besides using 13mg (0.024mmol) (1S) obtained in Preparation 133 - (3- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl) carbamic acid tert - butyl outside, in the same manner as in Example 22, to obtain 9mg (0.019mmol) of the title compound in 79% yield.

[1552] NMR:1H-NMR(CD3OD)δ4.92~4.79(2H,m),4.21~4.14(2H,m),3.97~3.92(2H,m),3.87~3.83(1H,m),3,71~3.68(1H,m),3.56~3.53(2H,m),3.37~3.33(2H,m),3.10~2.97(4H,m),2.83~2.70(1H,m),2.69~2.61(1H,m),1.39~1.35(3H,m),1.26(3H,d,J=6.4Hz) [1552] NMR: 1H-NMR (CD3OD) δ4.92 ~ 4.79 (2H, m), 4.21 ~ 4.14 (2H, m), 3.97 ~ 3.92 (2H, m), 3.87 ~ 3.83 (1H, m), 3 , 71 ~ 3.68 (1H, m), 3.56 ~ 3.53 (2H, m), 3.37 ~ 3.33 (2H, m), 3.10 ~ 2.97 (4H, m), 2.83 ~ 2.70 (1H, m), 2.69 ~ 2.61 ( 1H, m), 1.39 ~ 1.35 (3H, m), 1.26 (3H, d, J = 6.4Hz)

[1553] 质量(EI)430(M++1) [1553] mass (EI) 430 (M ++ 1)

[1554] 制备134:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氢代丙基}氨基甲酸叔-丁酯 [1554] Preparation 134: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2-isopropyl-4- ( trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} hydrogen carbamic acid tert - butyl ester

[1555] 除了利用制备57获得的34mg(0.10mmol)(3S)-3-[(叔-丁氧羧基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和26mg(0.092mmol)2-异丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备130的产物)之外,以制备45的相同方式,获得26mg(0.046mmol)标题化合物,收率50%。 [1555] Preparation 57 except using the obtained 34mg (0.10mmol) (3S) -3 - [(tert - butoxy carboxy) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 yl) butyric acid and 26mg (0.092mmol) 2- isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride (prepared addition product 130), in the same manner as in preparation 45 to give 26mg (0.046mmol) of the title compound in 50% yield.

[1556] 质量(EI)564(M++1) [1556] mass (EI) 564 (M ++ 1)

[1557] 实施例74:合成1-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮盐酸盐 [1557] Example 74: Synthesis of 1 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one hydrochloride

[1558] [1558]

[1559] 除了利用制备134获得的26mg(0.046mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得20mg(0.040mmol)标题化合物,收率86%。 [1559] Preparation 134 except for using the obtained 26mg (0.046mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 20mg (0.040mmol) of the title compound in 86% yield.

[1560] NMR:1H-NMR(CD3OD)δ4.79~4.68(2H,m),3.83~3.66(4H,m),3.55~3.48(2H,m),3.38~3.36(1H,m),3.15~3.07(1H,m),3.01~2.85(2H,m),2.69~2.64(1H,m),2.58~2.40(3H,m),2.29~2.19(2H,m),1.24~1.14(6H,m) [1560] NMR: 1H-NMR (CD3OD) δ4.79 ~ 4.68 (2H, m), 3.83 ~ 3.66 (4H, m), 3.55 ~ 3.48 (2H, m), 3.38 ~ 3.36 (1H, m), 3.15 ~ 3.07 (1H, m), 3.01 ~ 2.85 (2H, m), 2.69 ~ 2.64 (1H, m), 2.58 ~ 2.40 (3H, m), 2.29 ~ 2.19 (2H, m), 1.24 ~ 1.14 (6H, m)

[1561] 质量(EI)464(M++1) [1561] mass (EI) 464 (M ++ 1)

[1562] 制备135:合成(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1562] Preparation 135: Synthesis of (1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1563] 除了利用制备51获得的32.0mg(0.10mmol)(3S)-3-[(叔-丁氧羧基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和26mg(0.092mmol)2-异丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备130的产物)之外,以制备45的相同方式,获得24mg(0.044mmol)标题化合物,收率47%。 [1563] Preparation 51 except for using the obtained 32.0mg (0.10mmol) (3S) -3 - [(tert - butoxy carboxy) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 26mg (0.092mmol) 2- isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition salt (the product of preparation 130), 45 was prepared in the same manner to obtain 24mg (0.044mmol) of the title compound in 47% yield.

[1564] 质量(EI)542(M++1) [1564] mass (EI) 542 (M ++ 1)

[1565] 实施例75:合成1-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮盐酸盐 [1565] Example 75: Synthesis of 1 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methylpiperidin-2-one hydrochloride

[1566] [1566]

[1567] 除了利用制备135获得的24mg(0.044mmol)(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得18mg(0.037mmol)标题化合物,收率84%。 [1567] In addition to 135 prepared using the obtained 24mg (0.044mmol) (1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3- [2 - isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 22 to obtain 18mg (0.037mmol) of the title compound in 84% yield.

[1568] NMR:1H-NMR(CD3OD)δ4.86~4.78(2H,m),3.92~3.83(2H,m),3.67~3.62(1H,m),3.52~3.48(2H,m),3.41~3.37(1H,m),3.25~3.20(1H,m),3.25~3.20(2H,m),3.10~3.00(1H,m),2.78~2.72(1H,m),2.65~2.58(1H,m),2.46~2.32(2H,m),2.05~2.00(1H,m),1.87~1.80(1H,m),1.58~1.47(1H,m),1.36~1.36(6H,m),1.04(3H,d,J=6.8Hz) [1568] NMR: 1H-NMR (CD3OD) δ4.86 ~ 4.78 (2H, m), 3.92 ~ 3.83 (2H, m), 3.67 ~ 3.62 (1H, m), 3.52 ~ 3.48 (2H, m), 3.41 ~ 3.37 (1H, m), 3.25 ~ 3.20 (1H, m), 3.25 ~ 3.20 (2H, m), 3.10 ~ 3.00 (1H, m), 2.78 ~ 2.72 (1H, m), 2.65 ~ 2.58 (1H, m), 2.46 ~ 2.32 (2H, m), 2.05 ~ 2.00 (1H, m), 1.87 ~ 1.80 (1H, m), 1.58 ~ 1.47 (1H, m), 1.36 ~ 1.36 (6H, m), 1.04 ( 3H, d, J = 6.8Hz)

[1569] 质量(EI)442(M++1) [1569] mass (EI) 442 (M ++ 1)

[1570] 制备136:合成(1S)-1-{[(2R)-2-甲基-5-氧代吗啉-4-基]甲基}-3-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1570] Preparation 136: Synthesis of (1S) -1 - {[(2R) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1571] 除了利用制备55获得的32.0mg(0.10mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]丁酸和26mg(0.092mmol)2-异丙基]-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备130的产物)之外,以制备45的相同方式,获得24mg(0.044mmol)标题化合物,收率47%。 [1571] Preparation 55 except using the obtained 32.0mg (0.10mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo it 4-yl] butanoic acid and 26mg (0.092mmol) 2- isopropyl] - (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition salt (the product of preparation 130), 45 was prepared in the same manner to obtain 24mg (0.044mmol) of the title compound in 47% yield.

[1572] 质量(EI)544(M++1) [1572] mass (EI) 544 (M ++ 1)

[1573] 实施例76:合成(6S)-4-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮盐酸盐 [1573] Example 76: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one hydrochloride

[1574] [1574]

[1575] 除了利用制备136获得的24mg(0.044mmol)(1S)-1-{[(2R)-2-甲基-5-氧代吗啉-4-基]甲基}-3-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得21mg(0.043mmol)标题化合物,收率97%。 [1575] In addition to 136 prepared using the obtained 24mg (0.044mmol) (1S) -1 - {[(2R) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- [2 - isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 22 to obtain 21mg (0.043mmol) of the title compound in a yield of 97%.

[1576] NMR:1H-NMR(CD3OD)δ4.80~4.78(2H,m),4.20~4.08(2H,m),3.98~3.79(3H,m),3.59~3.52(2H,m),3.45~3.32(3H,m),3.25~3.20(1H,m),3.09~2.94(2H,m),2.74~2.69(1H,m),2.61~2.53(1H,m),1.36~1.34(6H,m),1.25(3H,d,J=6.4Hz) [1576] NMR: 1H-NMR (CD3OD) δ4.80 ~ 4.78 (2H, m), 4.20 ~ 4.08 (2H, m), 3.98 ~ 3.79 (3H, m), 3.59 ~ 3.52 (2H, m), 3.45 ~ 3.32 (3H, m), 3.25 ~ 3.20 (1H, m), 3.09 ~ 2.94 (2H, m), 2.74 ~ 2.69 (1H, m), 2.61 ~ 2.53 (1H, m), 1.36 ~ 1.34 (6H, m), 1.25 (3H, d, J = 6.4Hz)

[1577] 质量(EI)444(M++1) [1577] mass (EI) 444 (M ++ 1)

[1578] 制备137:合成{(1S)-1-{[(2R)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯 [1578] Preparation 137: Synthesis of {(1S) -1 - {[(2R) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester

[1579] 以制备24的相同方式,将制备24获得的300mg(0.77mmol)[1-甲酰基-3-氧代-3-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丙基]-1S-氨基甲酸叔-丁酯与152mg(0.77mmol)(R)-(2-氨基-1-甲基-乙氧基)-乙酸乙酯盐酸盐(制备119的产物)和325mg(1.54mmol)三乙酰氧硼氢化钠反应,得到150mg标题化合物,收率40%。 [1579] In the same manner as in Preparation 24, 300 mg of the preparation obtained in 24 (0.77mmol) [1- formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) - propyl] amino-1S-tert - butyl ester and 152mg (0.77mmol) (R) - (2- amino-1-methyl - ethoxy) - acetate hydrochloride (the product of preparation 119) and 325mg (1.54mmol) triacetoxy sodium borohydride, to give 150mg of the title compound in 40% yield.

[1580] 1H NMR(CDCl3)δ5.8-6.0(1H,m),4.8-5.1(2H,m),3.8-4.3(9H,m),3.6(1H,m),3.2-3.4(2H,m),2.7-2.9(1H,m),2.4-2.6(1H,m),1.40(9H,S),1.20(3H,br d,J=6.0Hz) [1580] 1H NMR (CDCl3) δ5.8-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (9H, m), 3.6 (1H, m), 3.2-3.4 (2H, m), 2.7-2.9 (1H, m), 2.4-2.6 (1H, m), 1.40 (9H, S), 1.20 (3H, br d, J = 6.0Hz)

[1581] 质量(m/e)491(M+1) [1581] mass (m / e) 491 (M + 1)

[1582] 实施例77:合成(6R)-4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮 [1582] Example 77: Synthesis of (6R) -4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2 , 4] triazolo [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methylmorpholine-3-one

[1583] [1583]

[1584] 除了利用制备137获得的150mg{(1S)-1-{[(2R)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯乙酸乙酯/盐酸之外,以实施例22的相同方式,获得80mg标题化合物,收率67%。 [1584] Besides using 150mg {(1S) -1 obtained in Preparation 137 - {[(2R) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} -carbamic acid tert - butyl outside ethyl acetate / hydrochloric acid in the same manner as Example 22 to obtain 80mg of the title compound in 67% yield.

[1585] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.1-4.4(4H,m),3.8-4.1(4H,m),3.3-3.5(2H,m),2.7-3.0(2H,m),1.22(3H,m) [1585] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.1-4.4 (4H, m), 3.8-4.1 (4H, m), 3.3-3.5 (2H, m), 2.7-3.0 ( 2H, m), 1.22 (3H, m)

[1586] 质量(m/e)391(M+1) [1586] mass (m / e) 391 (M + 1)

[1587] 制备138:合成{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯 [1587] Preparation 138: Synthesis of {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester

[1588] 除了利用制备55获得的115mg(0.36mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(2S)-2-甲基-5-氧代吗啉-4-基]-丁酸和参照WO 03/004498合成的70mg(0.36mmol)3-(三氟甲基)-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪之外,以制备45的相同方式,获得100mg标题化合物,收率56%。 [1588] Besides using 115mg (0.36mmol) (3S) -3 obtained in Preparation 55 - [(tert - butoxycarbonyl) amino] -4 - [(2S) -2- methyl-5-oxo-morpholine 4-yl] - butyric acid and with reference to WO 03/004498 synthetic 70mg (0.36mmol) 3- (trifluoromethyl) -5,6-dihydro--8H- [1,2,4] triazolo [ 4,3-a] pyrazine addition, in the same manner as in preparation 45, to obtain 100mg of the title compound in 56% yield.

[1589] 1H NMR(CDCl3)δ5.87(1H,m),4.8-5.1(2H,m),3.9-4.3(7H,m),3.8-3.9(1H,m),3.6-3.7(1H,m),3.2-3.4(3H,m),2.6-2.9(2H,m),1.39(9H,s),0.9(3H,br d,J=7.0Hz) [1589] 1H NMR (CDCl3) δ5.87 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (7H, m), 3.8-3.9 (1H, m), 3.6-3.7 (1H, m), 3.2-3.4 (3H, m), 2.6-2.9 (2H, m), 1.39 (9H, s), 0.9 (3H, br d, J = 7.0Hz)

[1590] 质量(m/e)491(M+1) [1590] mass (m / e) 491 (M + 1)

[1591] 实施例78:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮 [1591] Example 78: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2 , 4] triazolo [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methylmorpholine-3-one

[1592] [1592]

[1593] 除了将制备138获得的100mg{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯与乙酸乙酯/盐酸反应之外,以实施例22的相同方式,获得37mg标题化合物,收率47%。 [1593] In addition to 100mg {(1S) -1 obtained in the preparation of 138 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} -carbamic acid tert - addition of butyl / ethyl acetate to react with hydrochloric acid in the same manner as Example 22 to obtain 37mg of the title compound in 47% yield.

[1594] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.0-4.4(7H,m),3.8-4.0(2H,m),3.6-3.7(2H,m),3.3-3.4(2H,m),2.8-3.0(2H,m),1.3(3H,d,J=6.5Hz) [1594] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.0-4.4 (7H, m), 3.8-4.0 (2H, m), 3.6-3.7 (2H, m), 3.3-3.4 ( 2H, m), 2.8-3.0 (2H, m), 1.3 (3H, d, J = 6.5Hz)

[1595] 质量(m/e)391(M+1) [1595] mass (m / e) 391 (M + 1)

[1596] 制备139:合成{(1S)-1-{[(5S)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯 [1596] Preparation 139: Synthesis of {(1S) -1 - {[(5S) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester

[1597] 除了利用制备122获得的50mg(0.16mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5S)-5-甲基-2-氧代哌啶-1-基]-丁酸和参照WO 03/004498合成的31mg(0.16mmol)3-(三氟甲基)-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪之外,以制备45的相同方式,获得30mg标题化合物,收率38%。 [1597] Preparation 122 except for using the obtained 50mg (0.16mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5S) -5- methyl-2-oxopiperidine 1-yl] - butyric acid and with reference to WO 03/004498 synthetic 31mg (0.16mmol) 3- (trifluoromethyl) -5,6-dihydro--8H- [1,2,4] triazolo [ 4,3-a] pyrazine addition, in the same manner as in preparation 45, to obtain 30mg of the title compound in 38% yield.

[1598] 1H NMR(CDCl3)δ5.97(1H,m),4.8-5.1(2H,m),3.9-4.3(6H,m),3.3-3.7(3H,m),2.7-3.0(2H,m),2.2-2.5(3H,m),1.7-2.0(2H,m),1.39(9H,s),0.99(3H,br d,J=6.5Hz) [1598] 1H NMR (CDCl3) δ5.97 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (6H, m), 3.3-3.7 (3H, m), 2.7-3.0 (2H, m), 2.2-2.5 (3H, m), 1.7-2.0 (2H, m), 1.39 (9H, s), 0.99 (3H, br d, J = 6.5Hz)

[1599] 质量(m/e)489(M+1) [1599] mass (m / e) 489 (M + 1)

[1600] 实施例79:合成(5S)-1-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-5-甲基哌啶-2-酮 [1600] Example 79: Synthesis of (5S) -1 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2 , 4] triazolo [4,3-a] pyrazin -7 (8H) - yl] butyl} -5-methyl-piperidin-2-one

[1601] [1601]

[1602] 除了利用制备139获得的30mg{(1S)-1-{[(5S)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得11.6mg标题化合物,收率49%。 [1602] In addition to 30mg {(1S) -1 prepared using 139 obtained - {[(5S) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} -carbamic acid tert - butyl outside, in the same manner as in Example 22 to obtain 11.6mg of the title compound in 49% yield.

[1603] 1H NMR(CD3OD)δ4.9-5.1(2H,m),4.0-4.4(4H,m),3.7-3.9(2H,m),3.3-3.5(2H,m),2.7-3.1(3H,m),2.37(2H,br),1.9-2.1(1H,br s),1.8-1.9(1H,m),1.4-1.6(1H,m),1.03(3H,m) [1603] 1H NMR (CD3OD) δ4.9-5.1 (2H, m), 4.0-4.4 (4H, m), 3.7-3.9 (2H, m), 3.3-3.5 (2H, m), 2.7-3.1 ( 3H, m), 2.37 (2H, br), 1.9-2.1 (1H, br s), 1.8-1.9 (1H, m), 1.4-1.6 (1H, m), 1.03 (3H, m)

[1604] 质量(m/e)389(M+1) [1604] mass (m / e) 389 (M + 1)

[1605] 制备140:合成[(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5S)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [1605] Preparation 140: Synthesis of [(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - {[(5S) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[1606] 除了利用制备122获得的26mg(0.08mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5S)-5-甲基-2-氧代哌啶-1-基]-丁酸和25mg(0.08mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备127的产物)之外,以制备45的相同方式,获得3mg标题化合物,收率6.4%。 [1606] In addition to 122 prepared using the obtained 26mg (0.08mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5S) -5- methyl-2-oxopiperidine 1-yl] - butyric acid and 25mg (0.08mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride ( addition products of 127) was prepared in the same manner as in preparation 45 to give 3mg of the title compound in a yield of 6.4%.

[1607] 1H NMR(CDCl3)δ5.94(1H,m),4.8-5.1(2H,m),4.1-4.2(2H,m),3.7-3.8(2H,m),3.5-3.6(1H,m),3.3-3.5(2H,m),3.1-3.3(2H,m),2.8-3.0(1H,m),2.3-2.5(3H,m),1.8-2.0(2H,m),1.6-1.7(1H,m),1.40(9H,s),1.01(3H,d,J=7Hz) [1607] 1H NMR (CDCl3) δ5.94 (1H, m), 4.8-5.1 (2H, m), 4.1-4.2 (2H, m), 3.7-3.8 (2H, m), 3.5-3.6 (1H, m), 3.3-3.5 (2H, m), 3.1-3.3 (2H, m), 2.8-3.0 (1H, m), 2.3-2.5 (3H, m), 1.8-2.0 (2H, m), 1.6- 1.7 (1H, m), 1.40 (9H, s), 1.01 (3H, d, J = 7Hz)

[1608] 质量(m/e)568(M+1) [1608] mass (m / e) 568 (M + 1)

[1609] 实施例80:合成(5S)-1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1609] Example 80: Synthesis of (5S) -1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1610] [1610]

[1611] 除了利用制备140获得的3.0mg[(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5S)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得2.3mg标题化合物,收率93%。 [1611] Besides using 3.0mg [(1S) obtained in Preparation 140 3- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] -1 - outside butyl, - {[(5S) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamate in the same manner as in Example 22, to obtain 2.3mg of the title compound in 93% yield.

[1612] 1H NMR(CD3OD)δ4.8-5.0(2H,m),3.8-4.0(1H,m),3.3-3.7(5H,m),3.0-3.2(3H,m),2.5-2.7(2H,m),2.3-2.4(2H,m),1.8-2.0(2H,m),1.4-1.5(1H,m),1.02(3H,m) [1612] 1H NMR (CD3OD) δ4.8-5.0 (2H, m), 3.8-4.0 (1H, m), 3.3-3.7 (5H, m), 3.0-3.2 (3H, m), 2.5-2.7 ( 2H, m), 2.3-2.4 (2H, m), 1.8-2.0 (2H, m), 1.4-1.5 (1H, m), 1.02 (3H, m)

[1613] 质量(m/e)468(M+1) [1613] mass (m / e) 468 (M + 1)

[1614] 制备141:合成叔{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1614] Preparation 141: Synthesis of t {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3- [2-methyl-4 - (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1615] 除了利用制备51获得的131mg(0.418mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备126获得的106mg(0.418mmol)2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得137mg标题化合物,收率64%。 [1615] Besides using 131mg (0.418mmol) (3S) -3 obtained in Preparation 51 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 106mg (0.418mmol) obtained in preparation 126 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 137mg of the title compound in 64% yield.

[1616] 1H NMR(CDCl3)δ5.88(1H,brs),4.89-4.78(1H,m),4.76-4.64(1H,m),4.17-4.10(1H,m),3.78-3.73(1H,m),3.62-3.48(2H,m),3.39-3.33(1H,m),3.11-2.96(3H,m),2.84-2.79(1H,m),2.76(3H,s),2.60-2.20(3H,m),1.96-1.93(1H,m),1.84-1.81(1H,m),1.49-1.42(1H,m),1.40(9H,s),1.00(3H,d,J=6.8Hz) [1616] 1H NMR (CDCl3) δ5.88 (1H, brs), 4.89-4.78 (1H, m), 4.76-4.64 (1H, m), 4.17-4.10 (1H, m), 3.78-3.73 (1H, m), 3.62-3.48 (2H, m), 3.39-3.33 (1H, m), 3.11-2.96 (3H, m), 2.84-2.79 (1H, m), 2.76 (3H, s), 2.60-2.20 ( 3H, m), 1.96-1.93 (1H, m), 1.84-1.81 (1H, m), 1.49-1.42 (1H, m), 1.40 (9H, s), 1.00 (3H, d, J = 6.8Hz)

[1617] 质量(m/e)414(M+1-Boc) [1617] mass (m / e) 414 (M + 1-Boc)

[1618] 实施例81:合成(5R)-1-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1618] Example 81: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1619] [1619]

[1620] 除了利用制备141获得的137mg(0.267mmol){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例1的相同方式,获得99mg标题化合物,收率83%。 [1620] Besides using 137mg (0.267mmol) {(1S) -1 obtained in Preparation 141 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3- [ 2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 1 to obtain 99mg of the title compound in 83% yield.

[1621] 1H NMR(CD3OD)δ4.89-4.79(2H,m),3.94-3.91(1H,m),3.89-3.81(1H,m),3.77-3.73(1H,m),3.67-3.61(1H,m),3.56-3.52(1H,m),3.41-3.52(1H,m),3.14-3.08(2H,m),3.02-2.98(1H,m),2.90-2.66(2H,m),2.73(3H,s),2.50-2.33(2H,m),2.05-2.00(1H,m),1.89-1.84(1H,m),1.59-1.49(1H,m),1.07(3H,d,J=6.8Hz) [1621] 1H NMR (CD3OD) δ4.89-4.79 (2H, m), 3.94-3.91 (1H, m), 3.89-3.81 (1H, m), 3.77-3.73 (1H, m), 3.67-3.61 ( 1H, m), 3.56-3.52 (1H, m), 3.41-3.52 (1H, m), 3.14-3.08 (2H, m), 3.02-2.98 (1H, m), 2.90-2.66 (2H, m), 2.73 (3H, s), 2.50-2.33 (2H, m), 2.05-2.00 (1H, m), 1.89-1.84 (1H, m), 1.59-1.49 (1H, m), 1.07 (3H, d, J = 6.8Hz)

[1622] 质量(m/e)414(M+1) [1622] mass (m / e) 414 (M + 1)

[1623] 制备142:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯 [1623] Preparation 142: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester

[1624] 除了将制备51获得的64mg(0.205mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸与63mg(0.205mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备127的产物)反应之外,以制备42的相同方式,获得28mg标题化合物,收率24%。 [1624] except that 64mg (0.205mmol) (3S) obtained in Preparation 51 3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid and 63mg (0.205mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride (prepared addition product of 127) were reacted in the same manner as in preparation 42 to give the title compound 28mg, 24% yield.

[1625] 1H NMR(CDCl3)δ5.96-5.91(1H,m),5.08-4.88(1H,m),4.90-4.67(1H,m),4.15-4.10(1H,m),4.03-3.80(2H,m),3.62-3.57(1H,m),3.53-3.44(1H,m),3.40-3.31(1H,m),3.27-3.01(3H,m),2.90-2.79(1H,m),2.57-2.17(4H,m),1.94(1H,brs),1.81(1H,brs),1.42-1.40(9H,m),1.01(3H,d,J=6.4Hz) [1625] 1H NMR (CDCl3) δ5.96-5.91 (1H, m), 5.08-4.88 (1H, m), 4.90-4.67 (1H, m), 4.15-4.10 (1H, m), 4.03-3.80 ( 2H, m), 3.62-3.57 (1H, m), 3.53-3.44 (1H, m), 3.40-3.31 (1H, m), 3.27-3.01 (3H, m), 2.90-2.79 (1H, m), 2.57-2.17 (4H, m), 1.94 (1H, brs), 1.81 (1H, brs), 1.42-1.40 (9H, m), 1.01 (3H, d, J = 6.4Hz)

[1626] 质量(m/e)468(M+1-Boc) [1626] mass (m / e) 468 (M + 1-Boc)

[1627] 实施例82:合成(5R)-1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1627] Example 82: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1628] [1628]

[1629] 除了利用制备142获得的47mg(0.083mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例1的相同方式,获得33mg标题化合物,收率80%。 [1629] In addition to 142 prepared using the obtained 47mg (0.083mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 1 to obtain 33mg of the title compound in 80% yield.

[1630] 1H NMR(CD3OD)δ5.05-4.89(2H,m),3.98-3.90(2H,m),3.73-3.70(1H,m),3.64-3.49(2H,m),3.42-3.30(3H,m),3.24(1H,brs),3.13-3.05(2H,m),2.88-2.81(1H,m),2.75-2.62(1H,m),2.49-2.36(2H,m),2.03(1H,brs),1.86(1H,brs),1.60-1.48(1H,m),1.06(3H,d,J=6.4Hz) [1630] 1H NMR (CD3OD) δ5.05-4.89 (2H, m), 3.98-3.90 (2H, m), 3.73-3.70 (1H, m), 3.64-3.49 (2H, m), 3.42-3.30 ( 3H, m), 3.24 (1H, brs), 3.13-3.05 (2H, m), 2.88-2.81 (1H, m), 2.75-2.62 (1H, m), 2.49-2.36 (2H, m), 2.03 ( 1H, brs), 1.86 (1H, brs), 1.60-1.48 (1H, m), 1.06 (3H, d, J = 6.4Hz)

[1631] 质量(m/e)468(M+1) [1631] mass (m / e) 468 (M + 1)

[1632] 制备143:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1632] Preparation 143: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1633] 除了利用制备57获得的46.4mg(0.138mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸和42.5mg(0.138mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备127的产物)之外,以制备45的相同方式,获得42mg标题化合物,收率51%。 [1633] Preparation 57 except for using the obtained 46.4mg (0.138mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin - 1- yl) - butyric acid and 42.5mg (0.138mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride ( addition products of 127) was prepared in the same manner as in preparation 45 to give the title compound 42mg, 51% yield.

[1634] 1H NMR(CDCl3)δ5.83-5.79(1H,m),5.05-4.91(1H,m),4.89-4.78(1H,m),4.17(1H,brs),4.00-3.58(5H,m),3.52-3.48(1H,m),3.20-3.12(2H,m),2.85-2.78(1H,m),2.59-2.48(3H,m),2.29-2.25(2H,m),1.48-1.40(9H,m) [1634] 1H NMR (CDCl3) δ5.83-5.79 (1H, m), 5.05-4.91 (1H, m), 4.89-4.78 (1H, m), 4.17 (1H, brs), 4.00-3.58 (5H, m), 3.52-3.48 (1H, m), 3.20-3.12 (2H, m), 2.85-2.78 (1H, m), 2.59-2.48 (3H, m), 2.29-2.25 (2H, m), 1.48- 1.40 (9H, m)

[1635] 质量(m/e)490(M+1-Boc) [1635] mass (m / e) 490 (M + 1-Boc)

[1636] 实施例83:合成1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1636] Example 83: Synthesis of 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1637] [1637]

[1638] 除了利用制备143获得的42mg(0.071mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例1的相同方式,获得21mg标题化合物,收率56%。 [1638] In addition to 143 prepared using the obtained 42mg (0.071mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - outside butyl - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert , in the same manner as in Example 1 to obtain 21mg of the title compound in 56% yield.

[1639] 1H NMR(CD3OD)δ5.05-4.92(2H,m),3.98-3.91(2H,m),3.85-3.79(2H,m),3.70-3.59(2H,m),3.54-3.48(1H,m),3.36-3.33(2H,m),3.24(1H,brs),3.14(1H,brs),2.83-2.76(1H,m),2.72-2.53(3H,m),2.43-2.34(2H,m) [1639] 1H NMR (CD3OD) δ5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m), 3.70-3.59 (2H, m), 3.54-3.48 ( 1H, m), 3.36-3.33 (2H, m), 3.24 (1H, brs), 3.14 (1H, brs), 2.83-2.76 (1H, m), 2.72-2.53 (3H, m), 2.43-2.34 ( 2H, m)

[1640] 质量(m/e)490(M+1) [1640] mass (m / e) 490 (M + 1)

[1641] 制备144:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯 [1641] Preparation 144: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester

[1642] 除了利用制备55获得的43.7mg(0.138mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]-丁酸和42.5mg(0.138mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备127的产物)之外,以制备45的相同方式,获得14mg标题化合物,收率17%。 [1642] Preparation 55 except using the obtained 43.7mg (0.138mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 morpholin-4-yl] - butyric acid and 42.5mg (0.138mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine salt addition salt (the product of preparation 127), 45 was prepared in the same manner to obtain 14mg of the title compound in 17% yield.

[1643] 1H NMR(CDCl3)δ5.85-5.83(1H,m),5.09-4.92(1H,m),4.95-4.78(1H,m),4.23-4.08(3H,m),4.04-3.76(3H,m),3.73-3.66(1H,m),3.46-3.38(1H,m),3.36-3.21(2H,m),3.18-3.10(2H,m),2.96-2.81(1H,m),2.61-2.50(1H,m),1.43-1.41(9H,m),1.28-1.24(3H,m) [1643] 1H NMR (CDCl3) δ5.85-5.83 (1H, m), 5.09-4.92 (1H, m), 4.95-4.78 (1H, m), 4.23-4.08 (3H, m), 4.04-3.76 ( 3H, m), 3.73-3.66 (1H, m), 3.46-3.38 (1H, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (1H, m), 2.61-2.50 (1H, m), 1.43-1.41 (9H, m), 1.28-1.24 (3H, m)

[1644] 质量(m/e)470(M+1-Boc) [1644] mass (m / e) 470 (M + 1-Boc)

[1645] 实施例84:合成(6S)-4-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 [1645] Example 84: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[1646] 除了利用制备144获得的14mg(0.023mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例1的相同方式,获得6.9mg标题化合物,收率59%。 [1646] Besides using 14mg (0.023mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyridine was prepared and 144 obtained [3,4-d] pyrimidine -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 1 to obtain 6.9mg of the title compound in 59% yield.

[1647] 1H NMR(CD3OD)δ4.89-4.80(2H,m),4.16-4.06(3H,m),3.92-3.85(4H,m),3.55-3.50(2H,m),3.34-3.30(1H,m),3.19(1H,brs),3.09(1H,brs),2.70-2.61(1H,m),2.59-2.53(1H,m),1.23-1.20(3H,m) [1647] 1H NMR (CD3OD) δ4.89-4.80 (2H, m), 4.16-4.06 (3H, m), 3.92-3.85 (4H, m), 3.55-3.50 (2H, m), 3.34-3.30 ( 1H, m), 3.19 (1H, brs), 3.09 (1H, brs), 2.70-2.61 (1H, m), 2.59-2.53 (1H, m), 1.23-1.20 (3H, m)

[1648] 质量(m/e)470(M+1) [1648] mass (m / e) 470 (M + 1)

[1649] 制备145:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1649] Preparation 145: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2-methyl-4- (C fluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1650] 除了利用制备57获得的55.3mg(0.164mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸和制备126获得的41.7mg(0.164mmol)2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得51.6mg标题化合物,收率59%。 [1650] In addition to using Preparation 57 55.3mg (0.164mmol) (3S) -3 obtained - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin - 1- yl) - 41.7mg acid and obtained in preparation 126 (0.164 mmol) 2- methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d ] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give the title compound 51.6mg, yield 59%.

[1651] 1H NMR(CDCl3)δ5.79-5.76(1H,m),4.84-4.78(1H,m),4.69-4.61(1H,m),4.18(1H,brs),3.88-3.80(1H,m),3.76-3.65(3H,m),3.60-3.52(2H,m),3.02-2.95(3H,m),2.82-2.73(4H,m),2.57-2.49(3H,m),2.27-2.20(1H,m),1.38-1.37(9H,m) [1651] 1H NMR (CDCl3) δ5.79-5.76 (1H, m), 4.84-4.78 (1H, m), 4.69-4.61 (1H, m), 4.18 (1H, brs), 3.88-3.80 (1H, m), 3.76-3.65 (3H, m), 3.60-3.52 (2H, m), 3.02-2.95 (3H, m), 2.82-2.73 (4H, m), 2.57-2.49 (3H, m), 2.27- 2.20 (1H, m), 1.38-1.37 (9H, m)

[1652] 质量(m/e)436(M+1-Boc) [1652] mass (m / e) 436 (M + 1-Boc)

[1653] 实施例85:合成1-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1653] Example 85: Synthesis of 1 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1654] [1654]

[1655] 除了利用制备145获得的51.6mg(0.119mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得43mg标题化合物,收率78%。 [1655] Preparation 145 except for using the obtained 51.6mg (0.119mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2 - methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 43mg of the title compound in 78% yield.

[1656] 1H NMR(CD3OD)δ4.83-4.77(2H,m),3.89-3.74(4H,m),3.68-3.60(3H,m),3.47-3.43(1H,m),3.30(3H,s),3.06(1H,brs),2.97(1H,brs),2.67-2.54(2H,m),2.37-2.30(3H,m) [1656] 1H NMR (CD3OD) δ4.83-4.77 (2H, m), 3.89-3.74 (4H, m), 3.68-3.60 (3H, m), 3.47-3.43 (1H, m), 3.30 (3H, s), 3.06 (1H, brs), 2.97 (1H, brs), 2.67-2.54 (2H, m), 2.37-2.30 (3H, m)

[1657] 质量(m/e)436(M+1) [1657] mass (m / e) 436 (M + 1)

[1658] 制备146:合成{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1658] Preparation 146: Synthesis of {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1659] 除了将制备55获得的62.4mg(0.197mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]-丁酸与50mg(0.197mmol)2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备128的产物)反应之外,以制备45的相同方式,获得39.8mg标题化合物,收率39%。 [1659] except that 62.4mg (0.197mmol) (3S) obtained in Preparation 55 3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 morpholin-4-yl] - butyric acid and 50mg (0.197mmol) 2- methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride (the product of preparation 128) were reacted in the same manner as in preparation 45 to give 39.8mg of the title compound in 39% yield.

[1660] 1H NMR(CDCl3)δ5.82-5.77(1H,m),4.90-4.78(1H,m),4.75-4.63(1H,m),4.29-4.09(2H,m),3.95-3.82(2H,m),3.80(1H,brs),3.76-3.62(1H,m),3.53-3.45(1H,m),3.41-3.29(2H,m),3.10-2.96(2H,m),2.89-2.80(1H,m),2.76(3H,s),2.60-2.49(1H,m),1.43-1.42(9H,m),1.28-1.24(3H,m) [1660] 1H NMR (CDCl3) δ5.82-5.77 (1H, m), 4.90-4.78 (1H, m), 4.75-4.63 (1H, m), 4.29-4.09 (2H, m), 3.95-3.82 ( 2H, m), 3.80 (1H, brs), 3.76-3.62 (1H, m), 3.53-3.45 (1H, m), 3.41-3.29 (2H, m), 3.10-2.96 (2H, m), 2.89- 2.80 (1H, m), 2.76 (3H, s), 2.60-2.49 (1H, m), 1.43-1.42 (9H, m), 1.28-1.24 (3H, m)

[1661] 质量(m/e)470(M+1-Boc) [1661] mass (m / e) 470 (M + 1-Boc)

[1662] 实施例86:合成(6S)-4-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 [1662] Example 86: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[1663] [1663]

[1664] 除了利用制备146获得的39.8mg(0.077mmol){(1S)-1-{[(2S)-2-甲基-5-氧代吗啉4-基]甲基}-3-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得26.5mg标题化合物,收率76%。 [1664] In addition to 146 prepared using the obtained 39.8mg (0.077mmol) {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- [ 2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 22 to give the title compound 26.5mg, yield 76%.

[1665] 1H NMR(CD3OD)δ4.83-4.77(2H,m),4.18-4.07(3H,m),3.95-3.88(2H,m),3.83-3.81(1H,m),3.58-3.52(2H,m),3.38-3.29(1H,m),3.07(1H,brs),2.97(1H,brs),2.81-2.76(1H,m),2.70-2.69(3H,m),2.67-2.60(1H,m),1.23(3H,d,J=6.1Hz) [1665] 1H NMR (CD3OD) δ4.83-4.77 (2H, m), 4.18-4.07 (3H, m), 3.95-3.88 (2H, m), 3.83-3.81 (1H, m), 3.58-3.52 ( 2H, m), 3.38-3.29 (1H, m), 3.07 (1H, brs), 2.97 (1H, brs), 2.81-2.76 (1H, m), 2.70-2.69 (3H, m), 2.67-2.60 ( 1H, m), 1.23 (3H, d, J = 6.1Hz)

[1666] 质量(m/e)416(M+1) [1666] mass (m / e) 416 (M + 1)

[1667] 制备147:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1667] Preparation 147: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [4- (C fluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1668] 除了将制备57获得的16mg(0.067mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸与22.5mg(0.067mmol)4-三氟甲基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备49的产物)之外,以制备45的相同方式,获得16.4mg标题化合物,收率47%。 [1668] Preparation 57 except that the obtained 16mg (0.067mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) - butanoic acid and 22.5mg (0.067mmol) 4- trifluoromethyl-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride (the product of preparation 49) of in addition, in the same manner as in preparation 45 to give the title compound 16.4mg, 47% yield.

[1669] 1H NMR(CDCl3)δ9.16-9.15(1H,m),5.81-5.79(1H,m),4.95-4.84(1H,m),4.81-4.70(1H,m),4.22-4.13(1H,m),3.92-3.89(1H,m),3.79-3.69(3H,m),3.65-3.52(2H,m),3.15-3.10(1H,m),3.06(1H,brs),2.86-2.79(1H,m),2.62-2.52(3H,m),2.36-2.22(2H,m),1.42-1.41(9H,m) [1669] 1H NMR (CDCl3) δ9.16-9.15 (1H, m), 5.81-5.79 (1H, m), 4.95-4.84 (1H, m), 4.81-4.70 (1H, m), 4.22-4.13 ( 1H, m), 3.92-3.89 (1H, m), 3.79-3.69 (3H, m), 3.65-3.52 (2H, m), 3.15-3.10 (1H, m), 3.06 (1H, brs), 2.86- 2.79 (1H, m), 2.62-2.52 (3H, m), 2.36-2.22 (2H, m), 1.42-1.41 (9H, m)

[1670] 质量(m/e)422(M+1-BOC) [1670] mass (m / e) 422 (M + 1-BOC)

[1671] 实施例87:合成1-{(2S)-2-氨基-4-氧代-4-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1671] Example 87: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1672] [1672]

[1673] 除了利用制备147获得的16.4mg(0.032mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得9.7mg标题化合物,收率67%。 [1673] Besides using 16.4mg (0.032mmol) obtained in Preparation 147 {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo 3- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester addition to the same manner as Example 22, to obtain 9.7mg of the title compound in 67% yield.

[1674] 1H NMR(CD3OD)δ9.03-9.02(1H,m),4.84-4.73(2H,m),3.84-3.66(3H,m),3.62-3.48(3H,m),3.43-3.35(1H,m),3.06-3.03(1H,m),2.95(1H,brs),2.75-2.57(2H,m),2.55-2.42(2H,m),2.31-2.20(2H,m) [1674] 1H NMR (CD3OD) δ9.03-9.02 (1H, m), 4.84-4.73 (2H, m), 3.84-3.66 (3H, m), 3.62-3.48 (3H, m), 3.43-3.35 ( 1H, m), 3.06-3.03 (1H, m), 2.95 (1H, brs), 2.75-2.57 (2H, m), 2.55-2.42 (2H, m), 2.31-2.20 (2H, m)

[1675] 质量(m/e)422(M+1) [1675] mass (m / e) 422 (M + 1)

[1676] 制备148:合成{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1676] Preparation 148: Synthesis of {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1677] 除了将制备55获得的21mg(0.067mmol)(3S)-3-[(叔-丁氧基羰基)氨基-4-[2(S)-2-甲基-5-氧代吗啉-4-基]-丁酸与16mg(0.067mmol)4-三氟甲基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备49的产物)反应之外,以制备45的相同方式,获得16.4mg标题化合物,收率47%。 [1677] Preparation 55 except that the obtained 21mg (0.067mmol) (3S) -3 - [(tert - butoxycarbonyl) amino -4- [2 (S) -2- methyl-5-oxo-morpholine 4-yl] - butyric acid and 16mg (0.067mmol) 4- trifluoromethyl-5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride (the product of preparation 49) outside of the reaction, 45 was prepared in the same manner to obtain 16.4mg of the title compound in 47% yield.

[1678] 1H NMR(CDCl3)δ9.15-9.14(1H,m),5.83-5.78(1H,m),4.96-4.84(1H,m),4.82-4.70(1H,m),4.29-4.08(3H,m),3.93-3.83(2H,m),3.77(1H,brs),3.70-3.63(1H,m),3.40-3.31(1H,m),3.51-3.45(1H,m),3.40-3.31(2H,m),3.20-3.00(2H,m),2.61-2.50(1H,m),1.42-1.42(9H,m),1.28-1.26(3H,m) [1678] 1H NMR (CDCl3) δ9.15-9.14 (1H, m), 5.83-5.78 (1H, m), 4.96-4.84 (1H, m), 4.82-4.70 (1H, m), 4.29-4.08 ( 3H, m), 3.93-3.83 (2H, m), 3.77 (1H, brs), 3.70-3.63 (1H, m), 3.40-3.31 (1H, m), 3.51-3.45 (1H, m), 3.40- 3.31 (2H, m), 3.20-3.00 (2H, m), 2.61-2.50 (1H, m), 1.42-1.42 (9H, m), 1.28-1.26 (3H, m)

[1679] 质量(m/e)402(M+1-BOC) [1679] mass (m / e) 402 (M + 1-BOC)

[1680] 实施例88:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮 [1680] Example 88: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -6-methylmorpholine-3-one

[1681] [1681]

[1682] 除了利用制备148获得的10.5mg(0.021mmol){(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得6.7mg标题化合物,收率73%。 [1682] Besides using 10.5mg (0.021mmol) {(1S) obtained in Preparation 148 -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3- oxo-3- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester addition , in the same manner as in Example 22, to obtain 6.7mg of the title compound in 73% yield.

[1683] 1H NMR(CDCl3)δ9.11-9.10(1H,m),4.88-4.81(2H,m),4.17-4.08(3H,m),3.95-3.86(2H,m),3.85-3.81(1H,m),3.68-3.64(1H,m),3.53-3.50(2H,m),3.32-3.29(1H,m),3.12(1H,brs),3.02(1H,brs),2.80-2.75(1H,m),2.66-2.58(1H,m),1.23(3H,d,J=6.1Hz) [1683] 1H NMR (CDCl3) δ9.11-9.10 (1H, m), 4.88-4.81 (2H, m), 4.17-4.08 (3H, m), 3.95-3.86 (2H, m), 3.85-3.81 ( 1H, m), 3.68-3.64 (1H, m), 3.53-3.50 (2H, m), 3.32-3.29 (1H, m), 3.12 (1H, brs), 3.02 (1H, brs), 2.80-2.75 ( 1H, m), 2.66-2.58 (1H, m), 1.23 (3H, d, J = 6.1Hz)

[1684] 质量(m/e)402(M+1) [1684] mass (m / e) 402 (M + 1)

[1685] 制备149:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯 [1685] Preparation 149: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [3- (V fluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester

[1686] 除了将制备57获得的43mg(0.178mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸与参照JMC 2005,48,p141-151合成的43mg(0.178mmol)3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪反应之外,以制备45的相同方式,获得63mg标题化合物,收率63%。 [1686] Preparation 57 except that the obtained 43mg (0.178mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) butanoic acid with reference to JMC 2005,48, p141-151 synthetic 43mg (0.178mmol) 3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4, other than 3-a] pyrazine, prepared in the same manner as 45, to obtain 63mg of the title compound in 63% yield.

[1687] 1H NMR(CDCl3)δ5.90-5.88(1H,m),5.13-4.77(2H,m),4.31-4.27(2H,m),4.20-4.09(2H,m),4.00-3.86(1H,m),3.73-3.63(3H,m),3.48-3.31(1H,m),2.88-2.72(1H,m),2.62-2.49(2H,m),2.43-2.39(1H,m),2.24-2.17(2H,m),1.42(9H,s). [1687] 1H NMR (CDCl3) δ5.90-5.88 (1H, m), 5.13-4.77 (2H, m), 4.31-4.27 (2H, m), 4.20-4.09 (2H, m), 4.00-3.86 ( 1H, m), 3.73-3.63 (3H, m), 3.48-3.31 (1H, m), 2.88-2.72 (1H, m), 2.62-2.49 (2H, m), 2.43-2.39 (1H, m), 2.24-2.17 (2H, m), 1.42 (9H, s).

[1688] 质量(m/e)461(M+1-BOC) [1688] mass (m / e) 461 (M + 1-BOC)

[1689] 实施例89:合成1-{(2S)-2-氨基-4-氧代-4-[-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-5,5-二氟哌啶-2-酮 [1689] Example 89: Synthesis of 1 - {(2S) -2- amino-4-oxo-4 - [- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazole and [4,3-a] pyrazin -7 (8H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1690] [1690]

[1691] 除了利用制备149获得的63mg(0.112mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得24.7mg标题化合物,收率44%。 [1691] In addition to 149 prepared using the obtained 63mg (0.112mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo - 3- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} -carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 24.7mg of the title compound in 44% yield.

[1692] 1H NMR(CD3OD)δ5.12-5.00(2H,m),4.42-4.39(1H,m),4.30(1H,brs),4.21-4.02(2H,m),3.89-3.75(4H,m),3.62-3.54(1H,m),3.02-2.82(2H,m),2.65-2.56(2H,m),2.43-2.35(2H,m) [1692] 1H NMR (CD3OD) δ5.12-5.00 (2H, m), 4.42-4.39 (1H, m), 4.30 (1H, brs), 4.21-4.02 (2H, m), 3.89-3.75 (4H, m), 3.62-3.54 (1H, m), 3.02-2.82 (2H, m), 2.65-2.56 (2H, m), 2.43-2.35 (2H, m)

[1693] 质量(m/e)461(M+1) [1693] mass (m / e) 461 (M + 1)

[1694] 制备150:合成{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯 [1694] Preparation 150: Synthesis of {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester

[1695] 除了将制备55获得的56mg(0.178mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]-丁酸与参照JMC 2005,48,p141-151合成的43mg(0.178mmol)3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪反应之外,以制备45的相同方式,获得68mg标题化合物,收率71%。 [1695] Preparation 55 except that the obtained 56mg (0.178mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5-oxo it 4-yl] - butyric acid with reference to JMC 2005,48, p141-151 synthetic 43mg (0.178mmol) 3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazole and outside [4,3-a] pyrazine, prepared in the same manner as 45, to obtain 68mg of the title compound in 71% yield.

[1696] 1H NMR(CDCl3)δ5.90-5.88(1H,m),5.13-4.77(2H,m),4.29-4.09(5H,m),4.05-3.95(2H,m),3.86-3.69(2H,m),3.40-3.23(3H,m),2.91-2.72(1H,m),2.60-2.50(1H,m),1.42(9H,brs),1.27-1.25(3H,m) [1696] 1H NMR (CDCl3) δ5.90-5.88 (1H, m), 5.13-4.77 (2H, m), 4.29-4.09 (5H, m), 4.05-3.95 (2H, m), 3.86-3.69 ( 2H, m), 3.40-3.23 (3H, m), 2.91-2.72 (1H, m), 2.60-2.50 (1H, m), 1.42 (9H, brs), 1.27-1.25 (3H, m)

[1697] 质量(m/e)441(M+1-BOC) [1697] mass (m / e) 441 (M + 1-BOC)

[1698] 实施例90:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮 [1698] Example 90: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2 , 4] triazolo [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methylmorpholine-3-one

[1699] [1699]

[1700] 除了利用制备150获得的68mg(0.126mmol){(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得20.4mg标题化合物,收率30%。 [1700] Besides using 68mg (0.126mmol) {(1S) -1 obtained in Preparation 150 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo -3- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester addition, in the same manner as Example 22 to give 20.4mg of the title compound in 30% yield.

[1701] 1H NMR(CD3OD)δ5.11-5.00(2H,m),4.38(1H,brs),4.30(1H,brs),4.21-4.13(3H,m),4.10-4.05(2H,m),4.00-3.95(1H,m),3.80-3.75(1H,m),3.64-3.62(2H,m),3.36-3.33(1H,m),2.95-2.86(1H,m),2.82-2.76(1H,m),1.26(3H,d,J=6.0Hz) [1701] 1H NMR (CD3OD) δ5.11-5.00 (2H, m), 4.38 (1H, brs), 4.30 (1H, brs), 4.21-4.13 (3H, m), 4.10-4.05 (2H, m) , 4.00-3.95 (1H, m), 3.80-3.75 (1H, m), 3.64-3.62 (2H, m), 3.36-3.33 (1H, m), 2.95-2.86 (1H, m), 2.82-2.76 ( 1H, m), 1.26 (3H, d, J = 6.0Hz)

[1702] 质量(m/e)441(M+1) [1702] mass (m / e) 441 (M + 1)

[1703] 制备151:合成{(1S)-3-[2.4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(2-甲基-5-氧代硫代吗啉-4-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1703] Preparation 151: Synthesis of {(1S) -3- [2.4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] - 1 - [(2-methyl-5-oxo-thiomorpholin-4-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1704] 除了将制备125获得的25mg(0.075mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(2-甲基-5-氧代硫代吗啉-4-基)-丁酸与23mg(0.075mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备127的产物)反应之外,以制备45的相同方式,获得24.5mg标题化合物,收率56%。 [1704] Preparation 125 except that the obtained 25mg (0.075mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (2-methyl-5-oxo-thiomorpholine-4 - yl) - butanoic acid and 23mg (0.075mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride (preparation 127 addition product) were reacted in the same manner as in preparation 45 to give the title compound 24.5mg, 56% yield.

[1705] 1H NMR(CDCl3)δ5.91-5.81(1H,m),5.08-4.78(2H,m),4.13-3.98(1H,m),3.85-3.77(2H,m),3.70-3.66(2H,m),3.50-3.38(2H,m),3.27-3.22(3H,m),3.15-3.07(2H,m),2.88-2.81(1H,m),2.55-2.47(1H,m),1.42-1.40(9H,m),1.31-1.23(3H,m) [1705] 1H NMR (CDCl3) δ5.91-5.81 (1H, m), 5.08-4.78 (2H, m), 4.13-3.98 (1H, m), 3.85-3.77 (2H, m), 3.70-3.66 ( 2H, m), 3.50-3.38 (2H, m), 3.27-3.22 (3H, m), 3.15-3.07 (2H, m), 2.88-2.81 (1H, m), 2.55-2.47 (1H, m), 1.42-1.40 (9H, m), 1.31-1.23 (3H, m)

[1706] 质量(m/e)486(M+1-BOC) [1706] mass (m / e) 486 (M + 1-BOC)

[1707] 实施例91:合成4-{(2S)-2-氨基-4-[2.4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基硫代吗啉-3-酮 [1707] Example 91: Synthesis of 4 - {(2S) -2- amino-4- [2.4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -6-methyl-thiomorpholine-3-one

[1708] [1708]

[1709] 除了利用制备151获得的24.5mg(0.042mmol){(1S)-3-[2.4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(2-甲基-5-氧代硫代吗啉-4-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得14.6mg标题化合物,收率67%。 [1709] In addition to 151 prepared using the obtained 24.5mg (0.042mmol) {(1S) -3- [2.4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -1 - [(2-methyl-5-oxo-thiomorpholin-4-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 14.6mg of the title compound in 67% yield.

[1710] 1H NMR(CD3OD)δ5.00-4.85(2H,m),3.96-3.86(3H,m),3.71-3.59(2H,m),3.50-3.30(5H,m),3.22-3.19(1H,m),3.09(1H,brs),2.66-2.62(1H,m),2.60-2.50(1H,m),1.28-1.27(3H,m) [1710] 1H NMR (CD3OD) δ5.00-4.85 (2H, m), 3.96-3.86 (3H, m), 3.71-3.59 (2H, m), 3.50-3.30 (5H, m), 3.22-3.19 ( 1H, m), 3.09 (1H, brs), 2.66-2.62 (1H, m), 2.60-2.50 (1H, m), 1.28-1.27 (3H, m)

[1711] 质量(m/e)486(M+1) [1711] mass (m / e) 486 (M + 1)

[1712] 制备152:合成{(1S)-3-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]1-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1712] Preparation 152: Synthesis of {(1S) -3- [2- tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] 1-1-- [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1713] 除了将制备57获得的16.9mg(0.050mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸与13.0mg(0.050mmol)2-叔-丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备131的产物)反应之外,以制备45的相同方式,获得19mg标题化合物,收率66%。 [1713] Preparation 57 except that the obtained 16.9mg (0.050mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin - 1- yl) - butanoic acid and 13.0mg (0.050mmol) 2- tert - butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride (the product of preparation 131) were reacted in the same manner as in preparation 45 to give the title compound 19mg, yield 66%.

[1714] 1H NMR(CDCl3)δ5.76(1H,brs),4.82(1H,brs),4.72-4.63(1H,m),4.20(1H,brs),3.87-3.85(1H,m),3.78-3.68(3H,m),3.62-3.53(2H,m),3.03-2.97(1H,m),2.84-2.80(1H,m),2.58-2.53(4H,m),2.29-2.20(2H,m),1.41-1.38(18H,m) [1714] 1H NMR (CDCl3) δ5.76 (1H, brs), 4.82 (1H, brs), 4.72-4.63 (1H, m), 4.20 (1H, brs), 3.87-3.85 (1H, m), 3.78 -3.68 (3H, m), 3.62-3.53 (2H, m), 3.03-2.97 (1H, m), 2.84-2.80 (1H, m), 2.58-2.53 (4H, m), 2.29-2.20 (2H, m), 1.41-1.38 (18H, m)

[1715] 质量(m/e)475(M+1-BOC) [1715] mass (m / e) 475 (M + 1-BOC)

[1716] 实施例92:合成1-{(2S)-2-氨基-4-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1716] Example 92: Synthesis of 1 - {(2S) -2- amino-4- [2-tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1717] [1717]

[1718] 除了利用制备152获得的19mg(0.023mmol){(1S)-3-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]1-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得11.0mg标题化合物,收率92%。 [1718] Besides using 19mg (0.023mmol) {(1S) -3- [2- tert obtained in Preparation 152 - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] 1-1-- [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - addition butyl ester, in the same manner as in Example 22 to obtain 11.0mg of the title compound in 92% yield.

[1719] 1H NMR(CD3OD)δ4.86-4.79(2H,m),3.90-3.74(4H,m),3.50-3.43(1H,m),3.29(2H,brs),3.06(1H,brs),2.96(1H,brs),2.67-2.51(4H,m),2.35-2.30(2H,m),1.38-1.37(9H,m) [1719] 1H NMR (CD3OD) δ4.86-4.79 (2H, m), 3.90-3.74 (4H, m), 3.50-3.43 (1H, m), 3.29 (2H, brs), 3.06 (1H, brs) , 2.96 (1H, brs), 2.67-2.51 (4H, m), 2.35-2.30 (2H, m), 1.38-1.37 (9H, m)

[1720] 质量(m/e)478(M+1) [1720] mass (m / e) 478 (M + 1)

[1721] 制备153:合成[(1S)-3-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [1721] Preparation 153: Synthesis of [(1S) -3- [2- tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[1722] 除了将制备55获得的16mg(0.050mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]-丁酸与13mg(0.050mmol)2-叔-丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备131的产物)反应之外,以制备45的相同方式,获得18mg标题化合物,收率65%。 [1722] Preparation 55 except that the obtained 16mg (0.050mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5-oxo it 4-yl] - butyric acid and 13mg (0.050mmol) 2- tert - butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] addition pyrimidine hydrochloride (the product of preparation 131) were reacted in the same manner as in preparation 45 to give the title compound 18mg, 65% yield.

[1723] 1H NMR(CDCl3)δ5.75-5.74(1H,m),4.90-4.79(1H,m),4.65-4.60(1H,m),4.24-4.10(3H,m),3.92-3.87(2H,m),3.77-3.74(1H,m),3.67-3.62(1H,m),3.55-3.49(1H,m),3.40-3.31(2H,m),3.04-2.98(2H,m),2.86-2.83(1H,m),2.58-2.55(1H,m),1.43-1.42(9H,m),1.39-1.38(9H,s),1.28-1.24(3H,m) [1723] 1H NMR (CDCl3) δ5.75-5.74 (1H, m), 4.90-4.79 (1H, m), 4.65-4.60 (1H, m), 4.24-4.10 (3H, m), 3.92-3.87 ( 2H, m), 3.77-3.74 (1H, m), 3.67-3.62 (1H, m), 3.55-3.49 (1H, m), 3.40-3.31 (2H, m), 3.04-2.98 (2H, m), 2.86-2.83 (1H, m), 2.58-2.55 (1H, m), 1.43-1.42 (9H, m), 1.39-1.38 (9H, s), 1.28-1.24 (3H, m)

[1724] 质量(m/e)458(M+1-BOC) [1724] mass (m / e) 458 (M + 1-BOC)

[1725] 实施例93:合成(6S)-4-{(2S)-2-氨基-4-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮 [1725] Example 93: Synthesis of (6S) -4 - {(2S) -2- amino-4- [2-tert - butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methylmorpholine-3-one

[1726] [1726]

[1727] 除了利用制备153获得的18mg(0.022mmol)[(1S)-3-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得10.2mg标题化合物,收率94%。 [1727] Besides using 18mg (0.022mmol) [(1S) -3- [2- tert obtained in Preparation 153 - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- -d] pyrimidin -7 (6H) - yl] -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxopropyl] carbamate tert - butyl ester addition, in the same manner as in Example 22 to obtain 10.2mg of the title compound in 94% yield.

[1728] 1H NMR(CD3OD)δ4.86-4.75(2H,m),4.16-4.05(2H,m),3.94-3.89(1H,m),3.86-3.81(1H,m),3.55-3.50(2H,m),3.40-3.28(4H,m),3.07-3.05(1H,m),2.96(1H,brs),2.70-2.65(1H,m),2.57-2.52(1H,m),1.38-1.37(9H,m),1.22(3H,d,J=6.2Hz) [1728] 1H NMR (CD3OD) δ4.86-4.75 (2H, m), 4.16-4.05 (2H, m), 3.94-3.89 (1H, m), 3.86-3.81 (1H, m), 3.55-3.50 ( 2H, m), 3.40-3.28 (4H, m), 3.07-3.05 (1H, m), 2.96 (1H, brs), 2.70-2.65 (1H, m), 2.57-2.52 (1H, m), 1.38- 1.37 (9H, m), 1.22 (3H, d, J = 6.2Hz)

[1729] 质量(m/e)458(M+1) [1729] mass (m / e) 458 (M + 1)

[1730] 制备154:合成{(1S)-1-[(2-甲基-5-氧代硫代吗啉-4-基)甲基]-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯 [1730] Preparation 154: Synthesis of {(1S) -1 - [(2- methyl-5-oxo-thiomorpholin-4-yl) methyl] -3-oxo-3- [3- (C fluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} carbamic acid tert - butyl ester

[1731] 除了将制备125获得的25mg(0.075mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(2-甲基-5-氧代硫代吗啉-4-基)-丁酸与参照WO 03/004498合成的14.4mg(0.075mmol)3-(三氟甲基)-5,6-二氢-8H-1,2,4-三唑并[4,3-a]吡嗪反应之外,以制备45的相同方式,获得21mg标题化合物,收率55%。 [1731] Preparation 125 except that the obtained 25mg (0.075mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (2-methyl-5-oxo-thiomorpholine-4 - yl) - butanoic acid synthesized with reference to WO 03/004498 14.4mg (0.075mmol) 3- (trifluoromethyl) -5,6-dihydro -8H-1,2,4- triazolo [4, other than 3-a] pyrazine, prepared in the same manner as 45, to obtain 21mg of the title compound in 55% yield.

[1732] 1H NMR(CDCl3)δ5.95-5.86(1H,m),5.12-4.80(3H,m),4.30-4.06(3H,m),3.99-3.90(2H,m),3.67-3.53(2H,m),3.42-3.35(1H,m),3.30-3.06(3H,m),2.90-2.74(1H,m),2.52-2.47(1H,m),1.40(9H,s),1.29-1.28(3H,m) [1732] 1H NMR (CDCl3) δ5.95-5.86 (1H, m), 5.12-4.80 (3H, m), 4.30-4.06 (3H, m), 3.99-3.90 (2H, m), 3.67-3.53 ( 2H, m), 3.42-3.35 (1H, m), 3.30-3.06 (3H, m), 2.90-2.74 (1H, m), 2.52-2.47 (1H, m), 1.40 (9H, s), 1.29- 1.28 (3H, m)

[1733] 质量(m/e)407(M+1-BOC) [1733] mass (m / e) 407 (M + 1-BOC)

[1734] 实施例94:合成4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基硫代吗啉-3-酮 [1734] Example 94: Synthesis of 4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] oxazolo [4,3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-thiomorpholine-3-one

[1735] [1735]

[1736] 除了利用制备154获得的21mg(0.042mmol){(1S)-1-[(2-甲基-5-氧代硫代吗啉-4-基)甲基]-3-氧代-3-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得5.8mg标题化合物,收率34%。 [1736] In addition to 154 prepared using the obtained 21mg (0.042mmol) {(1S) -1 - [(2- methyl-5-oxo-thiomorpholin-4-yl) methyl] -3-oxo - 3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin -7 (8H) - yl] propyl} -carbamic acid tert - butyl ester addition, in the same manner as in Example 22, to obtain 5.8mg of the title compound in 34% yield.

[1737] 1H NMR(CD3OD)δ5.08-4.98(2H,m),4.34(1H,brs),4.26(1H,brs),4.20-4.06(2H,m),3.74-3.69(2H,m),3.62(1H,brs),3.50-3.37(4H,m),3.32-3.23(1H,m),2.08-2.75(1H,m),2.68-2.62(1H,m),.33-1.31(3H,m) [1737] 1H NMR (CD3OD) δ5.08-4.98 (2H, m), 4.34 (1H, brs), 4.26 (1H, brs), 4.20-4.06 (2H, m), 3.74-3.69 (2H, m) , 3.62 (1H, brs), 3.50-3.37 (4H, m), 3.32-3.23 (1H, m), 2.08-2.75 (1H, m), 2.68-2.62 (1H, m) ,. 33-1.31 (3H , m)

[1738] 质量(m/e)407(M+1) [1738] mass (m / e) 407 (M + 1)

[1739] 制备155:合成{(1S)-3-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯 [1739] Preparation 155: Synthesis of {(1S) -3- [2- ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester

[1740] 除了将制备51获得的66.3mg(0.211mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸与41mg(0.192mmol)2-乙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备128的产物)反应之外,以制备45的相同方式,获得63mg标题化合物,收率62%。 [1740] except that 66.3mg (0.211mmol) (3S) obtained in Preparation 51 3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxo-piperazine l-yl] butanoic acid and 41mg (0.192mmol) 2- ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition salt (the product of preparation 128) were reacted in the same manner as in preparation 45 to give the title compound 63mg, 62% yield.

[1741] 1H NMR(CDCl3)δ5.87(1H,brs),4.89-4.79(1H,m),4.76-4.65(1H,m),4.17(1H,brs),3.91-3.86(1H,m),3.78-3.75(1H,m),3.67-3.50(2H,m),3.89-3.35(1H,m),3.10-2.97(6H,m),2.88-2.81(1H,m),2.55-2.28(3H,m),1.95-1.88(1H,m),1.84-1.80(1H,m),1.42-1.40(9H,m),1.38-1.34(3H,m),1.01-0.99(3H,m) [1741] 1H NMR (CDCl3) δ5.87 (1H, brs), 4.89-4.79 (1H, m), 4.76-4.65 (1H, m), 4.17 (1H, brs), 3.91-3.86 (1H, m) , 3.78-3.75 (1H, m), 3.67-3.50 (2H, m), 3.89-3.35 (1H, m), 3.10-2.97 (6H, m), 2.88-2.81 (1H, m), 2.55-2.28 ( 3H, m), 1.95-1.88 (1H, m), 1.84-1.80 (1H, m), 1.42-1.40 (9H, m), 1.38-1.34 (3H, m), 1.01-0.99 (3H, m)

[1742] 质量(m/e)438(M+1-BOC) [1742] mass (m / e) 438 (M + 1-BOC)

[1743] 实施例95:合成(5R)-1-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1743] Example 95: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1744] [1744]

[1745] 除了利用制备155获得的63mg(0.119mmo1){(1S)-3-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得38.3mg标题化合物,收率69%。 [1745] Besides using 63mg (0.119mmo1) {(1S) -3- [2- ethyl-4- (trifluoromethyl) -5,8-dihydro-pyridine was prepared and 155 obtained [3,4-d ] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 22 to obtain 38.3mg of the title compound in 69% yield.

[1746] 1H NMR(CD3OD)δ4.92-4.80(2H,m),3.94-3.91(1H,m),3.88-3.85(1H,m),3.78-3.76(1H,m),3.69-3.62(1H,m),3.58-3.53(1H,m),3.42-3.34(2H,m),3.15-3.09(2H,m),3.03-2.97(2H,m),2.92-2.85(1H,m),2.79-2.73(1H,m),2.48-2.34(2H,m),2.06-2.02(1H,m),1.89-1.84(1H,m),1.60-1.49(1H,m),1.41-1.35(3H,m),1.05(3H,d,J=6.4Hz) [1746] 1H NMR (CD3OD) δ4.92-4.80 (2H, m), 3.94-3.91 (1H, m), 3.88-3.85 (1H, m), 3.78-3.76 (1H, m), 3.69-3.62 ( 1H, m), 3.58-3.53 (1H, m), 3.42-3.34 (2H, m), 3.15-3.09 (2H, m), 3.03-2.97 (2H, m), 2.92-2.85 (1H, m), 2.79-2.73 (1H, m), 2.48-2.34 (2H, m), 2.06-2.02 (1H, m), 1.89-1.84 (1H, m), 1.60-1.49 (1H, m), 1.41-1.35 (3H , m), 1.05 (3H, d, J = 6.4Hz)

[1747] 质量(m/e)428(M+1) [1747] mass (m / e) 428 (M + 1)

[1748] 制备156:合成{(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1748] Preparation 156: Synthesis of {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1749] 除了将制备51获得的43mg(0.137mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸(butryic acid)与40mg(0.125mmol)2-(五氟乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备129的产物)反应之外,以制备45的相同方式,获得65mg标题化合物,收率84%。 [1749] Preparation 51 except that the obtained 43mg (0.137mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid (butryic acid) and 40mg (0.125mmol) 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3, other than 4-d] pyrimidine hydrochloride (the product of preparation 129) were reacted in the same manner as in preparation 45 to give the title compound 65mg, yield 84%.

[1750] 1H NMR(CDCl3)δ5.98-5.91(1H,m),5.30-4.79(2H,m),4.14-4.02(2H,m),3.89-3.81(2H,m),3.69-3.47(2H,m),3.40-3.34(1H,m),3.24-3.01(3H,m),2.89-2.79(1H,m),2.57-2.43(1H,m),2.40-2.19(2H,m),1.94(1H,brs),1.84(1H,brs),1.42-1.40(9H,m),1.00(3H,d,J=6.4Hz) [1750] 1H NMR (CDCl3) δ5.98-5.91 (1H, m), 5.30-4.79 (2H, m), 4.14-4.02 (2H, m), 3.89-3.81 (2H, m), 3.69-3.47 ( 2H, m), 3.40-3.34 (1H, m), 3.24-3.01 (3H, m), 2.89-2.79 (1H, m), 2.57-2.43 (1H, m), 2.40-2.19 (2H, m), 1.94 (1H, brs), 1.84 (1H, brs), 1.42-1.40 (9H, m), 1.00 (3H, d, J = 6.4Hz)

[1751] 质量(m/e)518(M+1-BOC) [1751] mass (m / e) 518 (M + 1-BOC)

[1752] 实施例96:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [1752] Example 96: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5 , 8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[1753] [1753]

[1754] 除了利用制备156获得的65mg(0.104mmol){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得43.9mg标题化合物,收率82%。 [1754] Besides using 65mg (0.104mmol) {(1S) -1 obtained in Preparation 156 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo -3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 43.9mg of the title compound in 82% yield.

[1755] 1H NMR(CD3OD)δ4.99-4.95(1H,m),3.99-3.87(3H,m),3.69-3.68(1H,m),3.56-3.53(2H,m),3.41-3.38(1H,m),3.25(1H,brs),3.15-3.06(2H,m),2.84-2.77(1H,m),2.72-2.62(1H,m),2.45-2.34(2H,m),2.03(1H,brs),1.85(1H,brs),1.58-1.48(1H,m),1.05(3H,d,J=6.4Hz) [1755] 1H NMR (CD3OD) δ4.99-4.95 (1H, m), 3.99-3.87 (3H, m), 3.69-3.68 (1H, m), 3.56-3.53 (2H, m), 3.41-3.38 ( 1H, m), 3.25 (1H, brs), 3.15-3.06 (2H, m), 2.84-2.77 (1H, m), 2.72-2.62 (1H, m), 2.45-2.34 (2H, m), 2.03 ( 1H, brs), 1.85 (1H, brs), 1.58-1.48 (1H, m), 1.05 (3H, d, J = 6.4Hz)

[1756] 质量(m/e)518(M+1) [1756] mass (m / e) 518 (M + 1)

[1757] 制备157:合成{(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1757] Preparation 157: Synthesis of {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo-3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1758] 除了将制备55获得的43.3mg(0.137mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2(S)-2-甲基-5-氧代吗啉-4-基]-丁酸与40mg(0.125mmol)2-(五氟乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备129的产物)反应之外,以制备45的相同方式,获得58mg标题化合物,收率75%。 [1758] Preparation 55 except that the obtained 43.3mg (0.137mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2 (S) -2- methyl-5 morpholin-4-yl] - butyric acid and 40mg (0.125mmol) 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition pyrimidine hydrochloride (the product of preparation 129) to -d], in the same manner as in preparation 45, to obtain 58mg of the title compound in 75% yield.

[1759] 1H NMR(CDCl3)δ5.87-5.84(1H,m),5.09-4.79(2H,m),4.23-3.98(3H,m),3.89-3.80(2H,m),3.72-3.65(1H,m),3.46-3.33(4H,m),3.22-3.13(2H,m),2.90-2.81(1H,m),2.61-2.50(1H,m),1.43-1.41(9H,m),1.26(3H,d,J=6.0Hz) [1759] 1H NMR (CDCl3) δ5.87-5.84 (1H, m), 5.09-4.79 (2H, m), 4.23-3.98 (3H, m), 3.89-3.80 (2H, m), 3.72-3.65 ( 1H, m), 3.46-3.33 (4H, m), 3.22-3.13 (2H, m), 2.90-2.81 (1H, m), 2.61-2.50 (1H, m), 1.43-1.41 (9H, m), 1.26 (3H, d, J = 6.0Hz)

[1760] 质量(m/e)520(M+1-BOC) [1760] mass (m / e) 520 (M + 1-BOC)

[1761] 实施例97:合成(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮 [1761] Example 97: Synthesis of (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5 , 8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -6-methylmorpholine-3-one

[1762] [1762]

[1763] 除了利用制备157获得的58mg(0.094mmol){(1S)-1-{[(2S)-2-甲基-5-氧代吗啉-4-基]甲基}-3-氧代-3-[2-(五氟乙基)-4-(三氟)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得43.9mg标题化合物,收率90%。 [1763] Besides using 58mg (0.094mmol) obtained in Preparation 157 {(1S) -1 - {[(2S) -2- methyl-5-oxo-morpholin-4-yl] methyl} -3-oxo -3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 43.9mg of the title compound in 90% yield.

[1764] 1H NMR(CD3OD)δ4.99-4.95(1H,m),4.21-4.10(2H,m),4.05-3.90(3H,m),3.64-3.54(2H,m),3.50-3.39(2H,m),3.62-3.35(2H,m),3.24(1H,brs),3.14(1H,brs),2.79-2.73(1H,m),2.67-2.58(1H,m),1.26(3H,d,J=6.0Hz) [1764] 1H NMR (CD3OD) δ4.99-4.95 (1H, m), 4.21-4.10 (2H, m), 4.05-3.90 (3H, m), 3.64-3.54 (2H, m), 3.50-3.39 ( 2H, m), 3.62-3.35 (2H, m), 3.24 (1H, brs), 3.14 (1H, brs), 2.79-2.73 (1H, m), 2.67-2.58 (1H, m), 1.26 (3H, d, J = 6.0Hz)

[1765] 质量(m/e)520(M+1) [1765] mass (m / e) 520 (M + 1)

[1766] 制备158:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1766] Preparation 158: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [2- (E fluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1767] 除了将制备57获得的46mg(0.137mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)-丁酸与40mg(0.125mmol)2-(五氟乙基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(制备129的产物)反应之外,以制备45的相同方式,获得16.4mg标题化合物,收率47%。 [1767] Preparation 57 except that the obtained 46mg (0.137mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin -1 - yl) - butanoic acid and 40mg (0.125mmol) 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride (the product of preparation 129) were reacted in the same manner as in preparation 45 to give the title compound 16.4mg, 47% yield.

[1768] 1H NMR(CDCl3)δ5.85-5.78(1H,m),5.07-4.79(2H,m),4.17(1H,brs),4.04-3.61(5H,m),3.53-3.49(1H,m),3.19-3.13(2H,m),2.87-2.79(1H,m),2.62-2.48(3H,m),2.32-2.24(2H,m),1.42-1.41(9H,m) [1768] 1H NMR (CDCl3) δ5.85-5.78 (1H, m), 5.07-4.79 (2H, m), 4.17 (1H, brs), 4.04-3.61 (5H, m), 3.53-3.49 (1H, m), 3.19-3.13 (2H, m), 2.87-2.79 (1H, m), 2.62-2.48 (3H, m), 2.32-2.24 (2H, m), 1.42-1.41 (9H, m)

[1769] 质量(m/e)540(M+1-BOC) [1769] mass (m / e) 540 (M + 1-BOC)

[1770] 实施例98:合成1-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1770] Example 98: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1771] [1771]

[1772] 除了利用制备158获得的64mg(0.095mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得42.8mg标题化合物,收率83%。 [1772] In addition to 158 prepared using the obtained 64mg (0.095mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo - 3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 42.8mg of the title compound in 83% yield.

[1773] 1H NMR(CD3OD)δ4.98-4.95(1H,m),4.03-3.89(2H,m),3.85-3.77(2H,m),3.64-3.54(2H,m),3.52-3.46(1H,m),3.26-3.24(1H,m),3.14(1H,brs),2.80-2.72(1H,m),2.68-2.56(4H,m),2.04-2.03(2H,m) [1773] 1H NMR (CD3OD) δ4.98-4.95 (1H, m), 4.03-3.89 (2H, m), 3.85-3.77 (2H, m), 3.64-3.54 (2H, m), 3.52-3.46 ( 1H, m), 3.26-3.24 (1H, m), 3.14 (1H, brs), 2.80-2.72 (1H, m), 2.68-2.56 (4H, m), 2.04-2.03 (2H, m)

[1774] 质量(m/e)540(M+1) [1774] mass (m / e) 540 (M + 1)

[1775] 制备159:合成2-丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1775] Preparation 159: Synthesis of 2-propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1776] (1)合成丁烷酰亚胺酰胺 [1776] (1) Synthesis of butane polyimideamide

[1777] 除了利用2.0g(1.85mmol)丁腈之外,以制备58-(1)的相同方式,获得1.95g标题化合物,收率79%。 [1777] Besides using 2.0g (1.85mmol) butyronitrile addition, in the same manner as the preparation of 58- (1), to obtain 1.95g of the title compound in 79% yield.

[1778] NMR:1H-NMR(CD3OD)δ2.45(2H,t,J=6.5Hz),1.75(2H,m),1.05(3H,t,J=7.2Hz) [1778] NMR: 1H-NMR (CD3OD) δ2.45 (2H, t, J = 6.5Hz), 1.75 (2H, m), 1.05 (3H, t, J = 7.2Hz)

[1779] (2)合成2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1779] (2) Synthesis of 2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylic acid tert - butyl ester

[1780] 除了利用上述步骤(1)获得的500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和146mg(1.69mmol)丁烷酰亚胺酰胺之外,以制备58-(2)的相同方式,获得144mg标题化合物,收率25%。 [1780] In addition to the above steps 500mg (1.69mmol) 3- oxo (1) to obtain 4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - butyl ester and 146mg (1.69mmol) butane imido amine addition amide, was prepared in the same manner as 58- (2) to give the title compound 144mg, 25% yield.

[1781] 1H NMR(CDCl3)δ4.73(2H,s),3.76(2H,t,J=8.0Hz),3.00(4H,m),1.89(2H,m),1.54(9H,s),1.06(3H,t,J=8Hz) [1781] 1H NMR (CDCl3) δ4.73 (2H, s), 3.76 (2H, t, J = 8.0Hz), 3.00 (4H, m), 1.89 (2H, m), 1.54 (9H, s), 1.06 (3H, t, J = 8Hz)

[1782] 质量(m/e)346(M+1) [1782] mass (m / e) 346 (M + 1)

[1783] (3)2-丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1783] (3) 2-propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1784] 除了利用上述步骤(2)获得的144mg(0.42mmol)2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备58-(3)的相同方式,获得72mg标题化合物,收率61%。 [1784] In addition to the above steps (2) 144mg (0.42mmol) of 2- propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - carboxylic acid tert - butyl ester addition, in the same manner as the preparation of 58- (3), to obtain 72mg of the title compound in 61% yield.

[1785] 1H NMR(CD3OD)δ4.46(2H,s),3.59(2H,t,J=6.0Hz),3.25(2H,m),2.94(2H,t,J=7.2Hz),1.84(2H,m),0.97(3H,t,J=7.2Hz) [1785] 1H NMR (CD3OD) δ4.46 (2H, s), 3.59 (2H, t, J = 6.0Hz), 3.25 (2H, m), 2.94 (2H, t, J = 7.2Hz), 1.84 ( 2H, m), 0.97 (3H, t, J = 7.2Hz)

[1786] 质量(m/e)246(M+1) [1786] mass (m / e) 246 (M + 1)

[1787] 制备160:合成{(1S)-1-{[5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1787] Preparation 160: Synthesis of {(1S) -1 - {[5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo-3- [2- propoxy -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1788] 除了利用制备51获得的44.0mg(0.141mmole)(3S)-叔-[(叔-丁氧基羰基)氨基]-4-[(5R)-甲基-2-氧代哌啶-1-基]丁酸和制备159获得的36.0mg(0.128mmole)2-丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得70mg标题化合物,收率91%。 [1788] Preparation 51 except for using the obtained 44.0mg (0.141mmole) (3S) - tert - [(tert - butoxycarbonyl) amino] -4 - [(5R) - 2-oxo-piperidin - 1- yl] butanoic acid obtained in 159 and 36.0mg prepared (0.128mmole) 2- propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 70mg of the title compound in 91% yield.

[1789] 1H NMR(CDCl3)δ5.88(1H,brs),4.89-4.65(2H,m),4.18(1H,brs),3.89-3.86(1H,m),3.78-3.76(1H,m),3.62-51(2H,m),3.38-3.35(1H,m),3.11-2.80(7H,m),2.56-2.28(3H,m),1.94-1.82(4H,m),1.42-1.40(9H,m),1.01-0.98(6H,m) [1789] 1H NMR (CDCl3) δ5.88 (1H, brs), 4.89-4.65 (2H, m), 4.18 (1H, brs), 3.89-3.86 (1H, m), 3.78-3.76 (1H, m) , 3.62-51 (2H, m), 3.38-3.35 (1H, m), 3.11-2.80 (7H, m), 2.56-2.28 (3H, m), 1.94-1.82 (4H, m), 1.42-1.40 ( 9H, m), 1.01-0.98 (6H, m)

[1790] 质量(m/e)542(M+1) [1790] mass (m / e) 542 (M + 1)

[1791] 实施例99:合成(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮 [1791] Example 99: Synthesis of (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8- hydrogen pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one

[1792] [1792]

[1793] 除了利用制备160获得的70mg(0.129mmol){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得41.9mg标题化合物,收率68%。 [1793] In addition to 160 prepared using the obtained 70mg (0.129mmol) {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo -3- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl outside, in the same manner as in Example 22 to give the title compound 41.9mg, 68% yield.

[1794] 1H NMR(CD3OD)δ4.86-4.79(2H,m),3.95-3.82(2H,m),3.67-3.64(1H,m),3.59-3.47(2H,m),3.41-3.37(1H,m),3.34-3.32(1H,m),3.11-3.10(2H,m),3.01-2.93(2H,m),2.79-2.73(1H,m),2.67-2.57(1H,m),2.47-2.31(2H,m),2.04-2.00(1H,m),1.92-1.82(3H,m),1.58-1.48(1H,m),1.06(3H,d,J=6.4Hz),1.03-0.99(3H,m) [1794] 1H NMR (CD3OD) δ4.86-4.79 (2H, m), 3.95-3.82 (2H, m), 3.67-3.64 (1H, m), 3.59-3.47 (2H, m), 3.41-3.37 ( 1H, m), 3.34-3.32 (1H, m), 3.11-3.10 (2H, m), 3.01-2.93 (2H, m), 2.79-2.73 (1H, m), 2.67-2.57 (1H, m), 2.47-2.31 (2H, m), 2.04-2.00 (1H, m), 1.92-1.82 (3H, m), 1.58-1.48 (1H, m), 1.06 (3H, d, J = 6.4Hz), 1.03- 0.99 (3H, m)

[1795] 质量(m/e)442(M+1) [1795] mass (m / e) 442 (M + 1)

[1796] 制备161:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯 [1796] Preparation 161: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo-3- [2-propyl 4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester

[1797] 除了利用制备57获得的47.0mg(0.141mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备159获得的36.0mg(0.128mmol)2-丙基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得61mg标题化合物,收率77%。 [1797] Preparation 57 except for using the obtained 47.0mg (0.141mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidin - 1- yl) butyric acid and 159 preparation obtained 36.0mg (0.128mmol) 2- propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 61mg of the title compound in 77% yield.

[1798] 1H NMR(CDCl3)δ5.78(1H,brs),4.83-4.68(2H,m),4.20(1H,brs),3.88-3.68(4H,m),3.60-3.56(2H,m),3.04-2.78(5H,m),2.61-2.55(3H,m),2.31-2.23(2H,m),1.87-1.82(2H,m),1.42-1.41(9H,m),1.02-0.98(3H,m) [1798] 1H NMR (CDCl3) δ5.78 (1H, brs), 4.83-4.68 (2H, m), 4.20 (1H, brs), 3.88-3.68 (4H, m), 3.60-3.56 (2H, m) , 3.04-2.78 (5H, m), 2.61-2.55 (3H, m), 2.31-2.23 (2H, m), 1.87-1.82 (2H, m), 1.42-1.41 (9H, m), 1.02-0.98 ( 3H, m)

[1799] 质量(m/e)564(M+1) [1799] mass (m / e) 564 (M + 1)

[1800] 实施例100:合成1-{(2S)-2-氨基-4-氧代-4-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮 [1800] Example 100: Synthesis of 1 - {(2S) -2- amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one

[1801] [1801]

[1802] 除了利用制备161获得的47mg(0.081mmol){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代-3-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得34.4mg标题化合物,收率64%。 [1802] In addition to 161 prepared using the obtained 47mg (0.081mmol) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxo - 3- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 34.4mg of the title compound in 64% yield.

[1803] 1H NMR(CD3OD)δ4.90-4.79(2H,m),3.86-3.78(4H,m),3.57-3.46(3H,m),3.12-3.10(1H,m),3.00-2.93(3H,m),2.76-2.51(4H,m),2.41-2.31(2H,m),1.92-1.82(2H,m),1.03-0.95(3H,m) [1803] 1H NMR (CD3OD) δ4.90-4.79 (2H, m), 3.86-3.78 (4H, m), 3.57-3.46 (3H, m), 3.12-3.10 (1H, m), 3.00-2.93 ( 3H, m), 2.76-2.51 (4H, m), 2.41-2.31 (2H, m), 1.92-1.82 (2H, m), 1.03-0.95 (3H, m)

[1804] 质量(m/e)464(M+1) [1804] mass (m / e) 464 (M + 1)

[1805] 制备162:合成2-(氟甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1805] Preparation 162: Synthesis of 2- (fluoromethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1806] (1)合成2-氟乙烷酰亚胺酰胺 [1806] (1) Synthesis of 2-fluoro-ethane imide-amide

[1807] 除了利用1.5g(0.025mmol)氟代乙腈之外,以制备58-(1)的相同方式,获得1.77g标题化合物,收率93%。 [1807] Besides using 1.5g (0.025mmol) outside fluoro acetonitrile, prepared in the same manner as 58- (1), to obtain 1.77g of the title compound in 93% yield.

[1808] NMR:1H-NMR(CD3OD)δ5.32(2H,d,J=45.2Hz) [1808] NMR: 1H-NMR (CD3OD) δ5.32 (2H, d, J = 45.2Hz)

[1809] (2)合成2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯 [1809] (2) Synthesis of 2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxylate - butyl

[1810] 除了利用1.0g(3.39mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的335mg(4.40mmol)2-氟乙烷酰亚胺酰胺之外,以制备58-(2)的相同方式,获得220mg标题化合物,收率19%。 [1810] In addition to using 3-oxo 1.0g (3.39mmol) -4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 335mg ester and the above-described step (1) obtained in (4.40mmol) 2- fluoro addition to ethane polyimide amide, was prepared in the same manner as 58- (2) to give the title compound 220mg, 19% yield.

[1811] 1H NMR(CDCl3)δ5.55(2H,d,J=46.8Hz),4.78(2H,s),3.75(2H,t,J=6.0Hz),3.00(2H,brs),1.50(9H,s) [1811] 1H NMR (CDCl3) δ5.55 (2H, d, J = 46.8Hz), 4.78 (2H, s), 3.75 (2H, t, J = 6.0Hz), 3.00 (2H, brs), 1.50 ( 9H, s)

[1812] 质量(m/e)336(M+1) [1812] mass (m / e) 336 (M + 1)

[1813] (3)合成2-(氟甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1813] (3) Synthesis of 2- (fluoromethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1814] 除了利用上述步骤(2)获得的220mg(0.66mmol)2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔-丁酯之外,以制备58-(3)的相同方式,获得170mg标题化合物,收率96%。 [1814] 220mg (0.66mmol) except for using the above-described step (2) of 2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - carboxylic acid tert - butyl ester addition, in the same manner as the preparation of 58- (3), to obtain 170mg of the title compound in 96% yield.

[1815] 1H NMR(CD3OD)δ5.57(2H,d,J=29.6Hz),4.76(2H,s),4.47(2H,s),3.26-3.20(2H,m), [1815] 1H NMR (CD3OD) δ5.57 (2H, d, J = 29.6Hz), 4.76 (2H, s), 4.47 (2H, s), 3.26-3.20 (2H, m),

[1816] 质量(m/e)236(M+1) [1816] mass (m / e) 236 (M + 1)

[1817] 制备163:合成[(1S)-3-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基]氨基甲酸叔-丁酯 [1817] Preparation 163: Synthesis of [(1S) -3- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl] carbamic acid tert - butyl ester

[1818] 除了利用制备51获得的125mg(0.398mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备162获得的85mg(0.361mmole)2-(氟甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得115mg标题化合物,收率60%。 [1818] Preparation 51 except for using the obtained 125mg (0.398mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butanoic acid obtained in 162 and prepared 85mg (0.361mmole) 2- (fluoromethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition -d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 115mg of the title compound in 60% yield.

[1819] 1H NMR(CDCl3)δ5.90-5.88(1H,m),5.54(2H,dd,J=46.5,2.75Hz),4.97-4.72(2H,m),4.14(1H,brs),3.90(1H,brs),3.80-3.70(1H,m),3.55-3.52(2H,m),3.37-3.33(1H,m),3.10-2.98(3H,m),2.43-2.28(4H,m),1.45-1.38(9H,m),0.99(3H,d,J=6.8Hz) [1819] 1H NMR (CDCl3) δ5.90-5.88 (1H, m), 5.54 (2H, dd, J = 46.5,2.75Hz), 4.97-4.72 (2H, m), 4.14 (1H, brs), 3.90 (1H, brs), 3.80-3.70 (1H, m), 3.55-3.52 (2H, m), 3.37-3.33 (1H, m), 3.10-2.98 (3H, m), 2.43-2.28 (4H, m) , 1.45-1.38 (9H, m), 0.99 (3H, d, J = 6.8Hz)

[1820] 质量(m/e)532(M+1) [1820] mass (m / e) 532 (M + 1)

[1821] 实施例101:合成(5R)-1-{(2S)-2-氨基-4-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1821] Example 101: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyridine and [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1822] [1822]

[1823] 除了利用制备163获得的70mg(0.129mmole){(1S)-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代-3-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得41.9mg标题化合物,收率68%。 [1823] In addition to 163 prepared using the obtained 70mg (0.129mmole) {(1S) -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxo -3- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] propyl} -carbamic acid tert - butyl outside, in the same manner as in Example 22 to give the title compound 41.9mg, 68% yield.

[1824] 1H NMR(CD3OD)δ4.86-4.79(2H,m),3.95-3.82(2H,m),3.67-3.64(1H,m),3.59-3.47(2H,m),3.41-3.37(1H,m),3.34-3.32(1H,m),3.11-3.10(2H,m),3.01-2.93(2H,m),2.79-2.73(1H,m),2.67-2.57(1H,m),2.47-2.31(2H,m),2.04-2.00(1H,m),1.92-1.82(3H,m),1.58-1.48(1H,m),1.06(3H,d,J=6.4Hz),1.03-0.99(3H,m) [1824] 1H NMR (CD3OD) δ4.86-4.79 (2H, m), 3.95-3.82 (2H, m), 3.67-3.64 (1H, m), 3.59-3.47 (2H, m), 3.41-3.37 ( 1H, m), 3.34-3.32 (1H, m), 3.11-3.10 (2H, m), 3.01-2.93 (2H, m), 2.79-2.73 (1H, m), 2.67-2.57 (1H, m), 2.47-2.31 (2H, m), 2.04-2.00 (1H, m), 1.92-1.82 (3H, m), 1.58-1.48 (1H, m), 1.06 (3H, d, J = 6.4Hz), 1.03- 0.99 (3H, m)

[1825] 质量(m/e)432(M+1) [1825] mass (m / e) 432 (M + 1)

[1826] 制备164:合成{(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯 [1826] Preparation 164: Synthesis of {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (fluoromethyl) -4 - (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - butyl ester

[1827] 除了利用制备57的134mg(0.398mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备162获得的85.0mg(0.361mmole)2-(氟甲基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得85mg标题化合物,收率43%。 [1827] Preparation 57 except using 134mg (0.398mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 yl) butyric acid and 85.0mg (0.361mmole) 2- (fluoromethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro obtained 162 pyrido [3,4-d ] pyrimidine hydrochloride addition, in the same manner as in preparation 45, to obtain 85mg of the title compound in 43% yield.

[1828] 1H NMR(CDCl3)δ5.80-5.78(1H,brs),5.47(2H,d,J=24.4Hz),4.96-4.72(2H,m),4.18(1H,brs),3.91-3.89(1H,m),3.80-3.49(5H,m),3.11-3.00(2H,m),2.84-2.77(1H,m),2.59-2.48(3H,m),2.29-2.21(2H,m),1.42-1.40(9H,m) [1828] 1H NMR (CDCl3) δ5.80-5.78 (1H, brs), 5.47 (2H, d, J = 24.4Hz), 4.96-4.72 (2H, m), 4.18 (1H, brs), 3.91-3.89 (1H, m), 3.80-3.49 (5H, m), 3.11-3.00 (2H, m), 2.84-2.77 (1H, m), 2.59-2.48 (3H, m), 2.29-2.21 (2H, m) , 1.42-1.40 (9H, m)

[1829] 质量(m/e)554(M+1) [1829] mass (m / e) 554 (M + 1)

[1830] 实施例102:合成1-{(2S)-2-氨基-4-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1830] Example 102: Synthesis of 1 - {(2S) -2- amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1831] [1831]

[1832] 除了利用制备164获得的47mg(0.081mmole){(1S)-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得34.4mg标题化合物,收率64%。 [1832] Preparation 164 except for using the obtained 47mg (0.081mmole) {(1S) -1 - [(5,5- difluoro-2-oxo-piperidin-1-yl) methyl] -3- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxopropyl} carbamic acid tert - addition butyl ester, in the same manner as in Example 22 to obtain 34.4mg of the title compound in 64% yield.

[1833] 1H NMR(CD3OD)δ4.90-4.79(2H,m),3.86-3.78(4H,m),3.57-3.46(3H,m),3.12-3.10(1H,m),3.00-2.93(3H,m),2.76-2.51(4H,m),2.41-2.31(2H,m),1.92-1.82(2H,m),1.03-0.95(3H,m) [1833] 1H NMR (CD3OD) δ4.90-4.79 (2H, m), 3.86-3.78 (4H, m), 3.57-3.46 (3H, m), 3.12-3.10 (1H, m), 3.00-2.93 ( 3H, m), 2.76-2.51 (4H, m), 2.41-2.31 (2H, m), 1.92-1.82 (2H, m), 1.03-0.95 (3H, m)

[1834] 质量(m/e)464(M+1) [1834] mass (m / e) 464 (M + 1)

[1835] 制备165:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)丁酸叔-丁酯 [1835] Preparation 165: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-dihydro-pyrrol-1 -1H- - yl) -butyric acid tert - butyl ester

[1836] 除了利用3S-叔-丁氧基羰基氨基-4-氧代-丁酸叔-丁酯(制备41的产物)和制备6获得的590mg(3.56mmol)4-氨基-3-甲基-2-丁烯酸甲酯盐酸盐之外,以制备42的相同方式,获得410mg标题化合物,收率34%。 [1836] In addition to using 3S- tert - butoxycarbonylamino-4-oxo - butyric acid tert - butyl ester (the product of Preparation 41) and obtained in Preparation 6 590mg (3.56mmol) 4- amino-3-methyl addition of methyl-2-butene hydrochloride, in the same manner as in preparation 42, to obtain 410mg of the title compound in 34% yield.

[1837] 1H NMR(CDCl3)δ6.03(1H,s),5.34-5.31(1H,m),4.15-3.84(3H,m),3.71-3.62(1H,m),3.41-3.36(1H,m),2.54-2.38(2H,m),2.07-2.04(3H,m),1.45(9H,s),1.39(9H,s) [1837] 1H NMR (CDCl3) δ6.03 (1H, s), 5.34-5.31 (1H, m), 4.15-3.84 (3H, m), 3.71-3.62 (1H, m), 3.41-3.36 (1H, m), 2.54-2.38 (2H, m), 2.07-2.04 (3H, m), 1.45 (9H, s), 1.39 (9H, s)

[1838] 质量(m/e)355(M+1) [1838] mass (m / e) 355 (M + 1)

[1839] 制备166:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)丁酸 [1839] Preparation 166: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-dihydro-pyrrol-1 -1H- - yl) butyric acid

[1840] 除了利用制备165获得的410mg(1.16mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)丁酸叔-丁酯之外,以制备43的相同方式,获得310mg标题化合物,收率90%。 [1840] In addition to 165 prepared using the obtained 410mg (1.16mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-di hydrogen -1H- pyrrol-1-yl) butanoic acid tert - butyl ester addition, in the same manner as in preparation 43, to obtain 310mg of the title compound in 90% yield.

[1841] 1H NMR(CDCl3)δ9.03(1H,brs),6.12(1H,s),5.73(1H,d,J=8.8Hz),4.16-4.11(2H,m),3.94-3.90(1H,m),3.78-3.72(1H,m),3.50-3.45(1H,m),2.66-2.54(2H,m),2.07(3H,s),1.39(9H,s) [1841] 1H NMR (CDCl3) δ9.03 (1H, brs), 6.12 (1H, s), 5.73 (1H, d, J = 8.8Hz), 4.16-4.11 (2H, m), 3.94-3.90 (1H , m), 3.78-3.72 (1H, m), 3.50-3.45 (1H, m), 2.66-2.54 (2H, m), 2.07 (3H, s), 1.39 (9H, s)

[1842] 质量(m/e)299(M+1) [1842] mass (m / e) 299 (M + 1)

[1843] 制备167:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代吡咯烷-1-基)丁酸叔-丁酯 [1843] Preparation 167: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-pyrrolidin-1-yl) butanoic acid tert - butyl ester

[1844] 除了利用制备2获得的790mg(4.71mmol)4-氨基-3-甲基-丁酸甲酯盐酸盐之外,以制备42的相同方式,获得1.03g标题化合物,收率64%。 [1844] Preparation 2 except using the obtained 790mg (4.71mmol) 4- amino-3-methyl - butyric acid methyl ester hydrochloride addition, in the same manner as in Preparation 42 to give the title compound 1.03g, yield 64% .

[1845] 质量(m/e)357(M+1) [1845] mass (m / e) 357 (M + 1)

[1846] 制备168:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代吡咯烷-1-基)丁酸 [1846] Preparation 168: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-pyrrolidin-1-yl) butanoic acid

[1847] 除了利用制备167获得的1.03g(2.89mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代吡咯烷-1-基)丁酸叔-丁酯之外,以制备43的相同方式,获得670mg标题化合物,收率77%。 [1847] Preparation 167 except for using the obtained 1.03g (2.89mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-pyrrolidin-1 yl) butanoic acid tert - butyl ester addition, in the same manner as in preparation 43, to obtain 670mg of the title compound in 77% yield.

[1848] 1H NMR(CDCl3)δ6.96(1H,brs),5.97-5.55(1H,m),4.16(1H,brs),3.78-3.40(2H,m),3.27-2.99(1H,m),2.66-2.47(4H,m),2.14-2.05(1H,m),1.44-1.42(9H,s),1.12(3H,d,J=8.0Hz) [1848] 1H NMR (CDCl3) δ6.96 (1H, brs), 5.97-5.55 (1H, m), 4.16 (1H, brs), 3.78-3.40 (2H, m), 3.27-2.99 (1H, m) , 2.66-2.47 (4H, m), 2.14-2.05 (1H, m), 1.44-1.42 (9H, s), 1.12 (3H, d, J = 8.0Hz)

[1849] 质量(m/e)301(M+1) [1849] mass (m / e) 301 (M + 1)

[1850] 制备169:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-5-(三氟甲基)哌啶-1-基]丁酸叔-丁酯 [1850] Preparation 169: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidin-1-yl] butanoic acid tert - butyl ester

[1851] 除了利用制备11获得的132mg(0.558mmol)4-氨基甲基-5,5,5-三氟-戊酸甲酯盐酸盐之外,以制备42的相同方式,获得49mg标题化合物,收率22%。 [1851] Preparation 11 except for using the obtained 132mg (0.558mmol) 4- aminomethyl-5,5,5-trifluoro - pentanoic acid methyl ester hydrochloride addition, in the same manner as in Preparation 42 to give the title compound 49mg 22% yield.

[1852] 1H NMR(CDCl3)δ5.56-5.25(1H,m),4.40(1H,br s),3.85-3.46(1H,m),3.42-3.36(1H,m),3.32-2.27(1H,m),2.62-2.36(4H,m),2.13-2.05(2H,m),1.92-1.79(2H,m),1.46(9H,s),1.42-1.41(9H,m) [1852] 1H NMR (CDCl3) δ5.56-5.25 (1H, m), 4.40 (1H, br s), 3.85-3.46 (1H, m), 3.42-3.36 (1H, m), 3.32-2.27 (1H , m), 2.62-2.36 (4H, m), 2.13-2.05 (2H, m), 1.92-1.79 (2H, m), 1.46 (9H, s), 1.42-1.41 (9H, m)

[1853] 质量(m/e)425(M+1) [1853] mass (m / e) 425 (M + 1)

[1854] 制备170:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-5-(三氟甲基)哌啶-1-基]-丁酸 [1854] Preparation 170: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidin-1-yl] - butoxy acid

[1855] 除了利用制备169获得的49mg(0.115mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-5-(三氟甲基)哌啶-1-基]丁酸叔-丁酯之外,以制备43的相同方式,获得14mg标题化合物,收率13%。 [1855] Preparation 169 except for using the obtained 49mg (0.115mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidine 1-yl] butyric acid tert - butyl ester addition, in the same manner as in preparation 43, to obtain 14mg of the title compound in 13% yield.

[1856] 1H NMR(CDCl3)δ4.25(1H,br s),3.68-3.48(4H,m),2.83(2H,brs),2.56-2.36(2H,m),2.16-2.10(2H,m),1.96-1.84(2H,m),1.47-1.44(9H,s) [1856] 1H NMR (CDCl3) δ4.25 (1H, br s), 3.68-3.48 (4H, m), 2.83 (2H, brs), 2.56-2.36 (2H, m), 2.16-2.10 (2H, m ), 1.96-1.84 (2H, m), 1.47-1.44 (9H, s)

[1857] 质量(m/e)369(M+1) [1857] mass (m / e) 369 (M + 1)

[1858] 制备171.合成(3S)-3-[(叔-丁氢基羰基)氨基]-4-[2-氧代-4-(三氟甲基)吡咯烷-1-基]丁酸叔-丁酯 [1858] Preparation 171. Synthesis of (3S) -3 - [(tert - butyl hydrogen-ylcarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] butanoic acid tert - butyl ester

[1859] 除了利用制备1获得的390mg(1.65mmol)3-氨基甲基-4,4,4-三氟-丁酸乙酯盐酸盐之外,以制备42的相同方式,获得134mg标题化合物,收率21%。 [1859] Preparation 1 except using the obtained 390mg (1.65mmol) 3- aminomethyl-4,4,4-trifluoro - butanoate hydrochloride addition, in the same manner as in Preparation 42 to give the title compound 134mg in 21% yield.

[1860] 1H NMR(CDCl3)δ5.10-5.09(1H,brs),4.12(1H,br s),3.67-3.50(3H,m),3.28-3.25(1H,m),3.10-3.04(1H,m),2.64-2.50(2H,m),2.44-2.40(2H,m),1.47(9H,s),1.40(9H,s) [1860] 1H NMR (CDCl3) δ5.10-5.09 (1H, brs), 4.12 (1H, br s), 3.67-3.50 (3H, m), 3.28-3.25 (1H, m), 3.10-3.04 (1H , m), 2.64-2.50 (2H, m), 2.44-2.40 (2H, m), 1.47 (9H, s), 1.40 (9H, s)

[1861] 质量(m/e)411(M+1) [1861] mass (m / e) 411 (M + 1)

[1862] 制备172:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-4-(三氟甲基)吡咯烷-1-基]-丁酸 [1862] Preparation 172: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] - butoxy acid

[1863] 除了利用制备171的134mg(0-326mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-4-(三氟甲基)吡咯烷-1-基]丁酸叔-丁酯之外,以制备43的相同方式,获得89mg标题化合物,收率78%。 [1863] Preparation 171 except for using 134mg (0-326mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrolidine 1-yl] butyric acid tert - butyl ester addition, in the same manner as in preparation 43, to obtain 89mg of the title compound in 78% yield.

[1864] 质量(m/e)355(M+1) [1864] mass (m / e) 355 (M + 1)

[1865] 制备173:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代氧代哌啶-1-基)丁酸叔-丁酯 [1865] Preparation 173: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-piperidin-1-yl) butanoate - butyl

[1866] 除了利用制备8获得的620mg(3.43mmol)5-氨基-3-甲基-戊酸甲酯盐酸盐之外,以制备42的相同方式,获得750mg标题化合物,收率62%。 [1866] Preparation 8 except for using the obtained 620mg (3.43mmol) 5- amino-3-methyl - pentanoic acid methyl ester hydrochloride addition, in the same manner as in Preparation 42 to give the title compound 750mg, 62% yield.

[1867] 1H NMR(CDCl3)δ5.35-5.30(1H,m),4.17(1H,brs),3.95-3.86(1H,m),3.78-3.64(1H,m),3.51-3.46(1H,m),3.30-3.26(1H,m),3.16-3.02(1H,m),2.54-2.46(2H,m),2.41-2.34(1H,m),2.01-1.84(3H,m),1.45(9H,s),1.41(9H,s),1.01(3H,d,J=6.0Hz) [1867] 1H NMR (CDCl3) δ5.35-5.30 (1H, m), 4.17 (1H, brs), 3.95-3.86 (1H, m), 3.78-3.64 (1H, m), 3.51-3.46 (1H, m), 3.30-3.26 (1H, m), 3.16-3.02 (1H, m), 2.54-2.46 (2H, m), 2.41-2.34 (1H, m), 2.01-1.84 (3H, m), 1.45 ( 9H, s), 1.41 (9H, s), 1.01 (3H, d, J = 6.0Hz)

[1868] 质量(m/e)371(M+1) [1868] mass (m / e) 371 (M + 1)

[1869] 制备174:合成(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代哌啶-1-基)-丁酸 [1869] Preparation 174: Synthesis of (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-piperidin-1-yl) - butanoic acid

[1870] 除了利用制备173获得的750mg(2.02mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代氧代哌啶-1-基)丁酸叔-丁酯之外,以制备43的相同方式,获得579mg标题化合物,收率92%。 [1870] In addition to 173 prepared using the obtained 750mg (2.02mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-piperidin -1 - yl) butanoic acid tert - butyl ester addition, in the same manner as in preparation 43, to obtain 579mg of the title compound in 92% yield.

[1871] 1H NMR(CDCl3)δ7.93(1H,brs),5.05-5.57(1H,m),4.20-4.19(1H,m),3.90-3.74(1H,m),3.57-3.51(1H,m),3.41-3.23(2H,m),2.66-2.52(3H,m),2.07-1.86(3H,m),1.33(9H,s),1.01(3H,d,J=6.4Hz) [1871] 1H NMR (CDCl3) δ7.93 (1H, brs), 5.05-5.57 (1H, m), 4.20-4.19 (1H, m), 3.90-3.74 (1H, m), 3.57-3.51 (1H, m), 3.41-3.23 (2H, m), 2.66-2.52 (3H, m), 2.07-1.86 (3H, m), 1.33 (9H, s), 1.01 (3H, d, J = 6.4Hz)

[1872] 质量(m/e)315(M+1) [1872] mass (m / e) 315 (M + 1)

[1873] 制备175:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1873] Preparation 175: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - [(4-methyl-2-oxo-2,5-dihydro -1H- pyrrol-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1874] 除了利用制备166的25.0mg(0.084mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)丁酸和制备127获得的25.8mg(0.084mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得45.0mg标题化合物,收率98%。 [1874] In addition to 166 prepared using 25.0mg (0.084mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-di hydrogen -1H- pyrrol-1-yl) butyric acid and 25.8mg (0.084mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro obtained 127 pyrido [3, 4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give 45.0mg of the title compound in 98% yield.

[1875] 1H NMR(CDCl3)δ6.12-5.99(1H,m),5.79(1H,d,J=16.0Hz),5.09-4.84(2H,m),4.18-4.13(1H,m),4.07-3.91(3H,m),3.74-3.66(1H,m),3.58-3.53(1H,m),3.30-3.13(3H,m),2.95-2.83(1H,m),2.60-2.55(1H,m),2.09(3H,d,J=1.2Hz),1.45-1.43(9H,m) [1875] 1H NMR (CDCl3) δ6.12-5.99 (1H, m), 5.79 (1H, d, J = 16.0Hz), 5.09-4.84 (2H, m), 4.18-4.13 (1H, m), 4.07 -3.91 (3H, m), 3.74-3.66 (1H, m), 3.58-3.53 (1H, m), 3.30-3.13 (3H, m), 2.95-2.83 (1H, m), 2.60-2.55 (1H, m), 2.09 (3H, d, J = 1.2Hz), 1.45-1.43 (9H, m)

[1876] 质量(m/e)552(M+1) [1876] mass (m / e) 552 (M + 1)

[1877] 实施例103:合成1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基-1,5-二氢-2H-吡咯-2-酮 [1877] Example 103: Synthesis of 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -4-methyl-1,5-dihydro -2H- pyrrol-2-one

[1878] [1878]

[1879] 除了利用制备175获得的45.0mg(0.0816mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得25.7mg标题化合物,收率65%。 [1879] In addition to 175 prepared using the obtained 45.0mg (0.0816mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -1 - [(4-methyl-2-oxo-2,5-dihydro -1H- pyrrol-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as Example 22 to give the title compound 25.7mg, yield 65%.

[1880] 1H NMR(CD3OD)δ5.86-5.84(1H,m),4.99-4.97(2H,m),4.14-4.13(2H,m),4.10-3.91(3H,m),3.78-3.70(2H,m),3.25(1H,brs),3.14(1H,brs),3.10-3.00(1H,m),2.88-2.82(1H,m),2.14(3H,s) [1880] 1H NMR (CD3OD) δ5.86-5.84 (1H, m), 4.99-4.97 (2H, m), 4.14-4.13 (2H, m), 4.10-3.91 (3H, m), 3.78-3.70 ( 2H, m), 3.25 (1H, brs), 3.14 (1H, brs), 3.10-3.00 (1H, m), 2.88-2.82 (1H, m), 2.14 (3H, s)

[1881] 质量(m/e)452(M+1) [1881] mass (m / e) 452 (M + 1)

[1882] 制备176:合成{(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1882] Preparation 176: Synthesis of {(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -1 - [(4-methyl-2-oxo-2,5-dihydro -1H- pyrrol-1-yl) methyl] -3-oxopropyl} carbamate tert - butyl ester

[1883] 除了利用制备166获得的25mg(0.084mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)丁酸和制备96获得的25.6mg(0.084mmol)2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得44.9mg标题化合物,收率97%。 [1883] In addition to 166 prepared using the obtained 25mg (0.084mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-di hydrogen -1H- pyrrol-1-yl) butyric acid and 25.6 mg obtained in preparation 96 (0.084mmol) 2- (3- furyl) -4- (trifluoromethyl) -5,6,7,8- hydrogen pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give the title compound 44.9mg, yield 97%.

[1884] 1H NMR(CDCl3)δ8.27(1H,s),7.50-7.49(1H,m),7.06-7.05(1H,m),6.04-5.90(1H,m),5.80-5.79(1H,m),4.85(1H,s),4.83-4.70(1H,m),4.15-4.07(1H,m),4.02-3.95(2H,m),3.92-3.87(1H,m),3.84-3.81(1H,m),3.69-3.55(2H,m),3.08-3.06(1H,m),2.99(1H,brs),2.91-2.83(1H,m),2.57-2.52(1H,m),2.05-2.04(3H,m),1.41-1.40(9H,m) [1884] 1H NMR (CDCl3) δ8.27 (1H, s), 7.50-7.49 (1H, m), 7.06-7.05 (1H, m), 6.04-5.90 (1H, m), 5.80-5.79 (1H, m), 4.85 (1H, s), 4.83-4.70 (1H, m), 4.15-4.07 (1H, m), 4.02-3.95 (2H, m), 3.92-3.87 (1H, m), 3.84-3.81 ( 1H, m), 3.69-3.55 (2H, m), 3.08-3.06 (1H, m), 2.99 (1H, brs), 2.91-2.83 (1H, m), 2.57-2.52 (1H, m), 2.05- 2.04 (3H, m), 1.41-1.40 (9H, m)

[1885] 质量(m/e)550(M+1) [1885] mass (m / e) 550 (M + 1)

[1886] 实施例104:合成1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基-1,5-二氢-2H-吡咯-2-酮 [1886] Example 104: Synthesis of 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-1,5-dihydro -2H- pyrrol-2-one

[1887] [1887]

[1888] 除了利用制备176获得的44.9mg(0.0817mmol){(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代-2,5-二氢-1H-吡咯-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得32.7mg标题化合物,收率82%。 [1888] In addition to 176 prepared using the obtained 44.9mg (0.0817mmol) {(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -1 - [(4-methyl-2-oxo-2,5-dihydro -1H- pyrrol-1-yl) methyl] -3 - oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 32.7mg of the title compound in 82% yield.

[1889] 1H NMR(CD3OD)δ8.35(1H,s),7.69-7.64(1H,m),7.08(1H,s),6.10(1H,brs),4.90-4.88(2H,m),4.23(1H,brs),3.95-3.81(5H,m),3.77-3.65(1H,m),3.19-3.03(3H,m),2.94-2.87(1H,m),2.15(3H,m) [1889] 1H NMR (CD3OD) δ8.35 (1H, s), 7.69-7.64 (1H, m), 7.08 (1H, s), 6.10 (1H, brs), 4.90-4.88 (2H, m), 4.23 (1H, brs), 3.95-3.81 (5H, m), 3.77-3.65 (1H, m), 3.19-3.03 (3H, m), 2.94-2.87 (1H, m), 2.15 (3H, m)

[1890] 质量(m/e)450(M+1) [1890] mass (m / e) 450 (M + 1)

[1891] 制备177:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代吡咯烷-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1891] Preparation 177: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - [(4-methyl-2-oxo-pyrrolidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1892] 除了利用制备168获得的35.0mg(0.117mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代吡咯烷-1-基)丁酸和制备127获得的33.0mg(0.106mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得13.0mg标题化合物,收率20%。 [1892] In addition to 168 prepared using the obtained 35.0mg (0.117mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-pyrrolidin-1 33.0mg-yl) butyric acid and obtained in preparation 127 (0.106 mmol) 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give the title compound 13.0mg, yield 20%.

[1893] 1H NMR(CDCl3)δ5.78-5.75(1H,m),5.06-4.80(2H,m),4.15-4.09(1H,m),3.98-3.85(2H,m),3.65-3.55(1H,m),3.46-3.44(2H,m),3.19-3.06(3H,m),2.87-2.76(1H,m),2.59-2.45(3H,m),2.04-1.94(1H,m),1.42-1.40(9H,m),1.12-1.11(3H,m) [1893] 1H NMR (CDCl3) δ5.78-5.75 (1H, m), 5.06-4.80 (2H, m), 4.15-4.09 (1H, m), 3.98-3.85 (2H, m), 3.65-3.55 ( 1H, m), 3.46-3.44 (2H, m), 3.19-3.06 (3H, m), 2.87-2.76 (1H, m), 2.59-2.45 (3H, m), 2.04-1.94 (1H, m), 1.42-1.40 (9H, m), 1.12-1.11 (3H, m)

[1894] 质量(m/e)552(M+1) [1894] mass (m / e) 552 (M + 1)

[1895] 实施例105:合成1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基氧代吡咯烷-2-酮 [1895] Example 105: Synthesis of 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -4-methyl-2-oxo-pyrrolidin

[1896] [1896]

[1897] 除了利用制备177获得的13.0mg(0.0235mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代吡咯烷-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得10.0mg标题化合物,收率87%。 [1897] Preparation 177 except for using the obtained 13.0mg (0.0235mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -1 - [(4-methyl-2-oxo-pyrrolidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 10.0mg of the title compound in 87% yield.

[1898] 1H NMR(CD3OD)δ5.05-4.97(2H,m),3.99(1H,brs),3.91-3.88(2H,m),3.77-3.73(1H,m),3.61-3.59(1H,m),3.48-3.45(1H,m),3.25(1H,brs),3.15(2H,brs),3.05-2.98(1H,m),2.89-2.79(1H,m),2.58-2.53(2H,m),2.12-2.07(1H,m),1.17-1.63(3H,m) [1898] 1H NMR (CD3OD) δ5.05-4.97 (2H, m), 3.99 (1H, brs), 3.91-3.88 (2H, m), 3.77-3.73 (1H, m), 3.61-3.59 (1H, m), 3.48-3.45 (1H, m), 3.25 (1H, brs), 3.15 (2H, brs), 3.05-2.98 (1H, m), 2.89-2.79 (1H, m), 2.58-2.53 (2H, m), 2.12-2.07 (1H, m), 1.17-1.63 (3H, m)

[1899] 质量(m/e)452(M+1) [1899] mass (m / e) 452 (M + 1)

[1900] 制备178.合成{(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代吡咯烷-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1900] Preparation 178. Synthesis of {(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -1 - [(4-methyl-2-oxo-pyrrolidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1901] 除了利用制备168获得的35.0mg(0.117mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代吡咯烷-1-基)丁酸和制备96获得的32.4mg(0.117mmol)2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得26.0mg标题化合物,收率44%。 [1901] In addition to 168 prepared using the obtained 35.0mg (0.117mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-pyrrolidin-1 yl) butyric acid and 96 obtained in preparation 32.4mg (0.117mmol) 2- (3- furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- d] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give 26.0mg of the title compound in 44% yield.

[1902] 1H NMR(CDCl3)δ8.27(1H,s),7.50(1H,s),7.06(1H,s),5.76-5.70(1H,m),4.86(1H,s),4.80-4.69(1H,m),4.15-4.09(1H,m),3.91-3.88(1H,m),3.80-3.79(1H,m),3.67-3.42(3H,m),3.09-3.00(3H,m),2.87-2.79(1H,m),2.58-2.35(3H,m),2.02-1.97(1H,m),1.42-1.41(9H,m),1.11(3H,d,J=6.0Hz) [1902] 1H NMR (CDCl3) δ8.27 (1H, s), 7.50 (1H, s), 7.06 (1H, s), 5.76-5.70 (1H, m), 4.86 (1H, s), 4.80-4.69 (1H, m), 4.15-4.09 (1H, m), 3.91-3.88 (1H, m), 3.80-3.79 (1H, m), 3.67-3.42 (3H, m), 3.09-3.00 (3H, m) , 2.87-2.79 (1H, m), 2.58-2.35 (3H, m), 2.02-1.97 (1H, m), 1.42-1.41 (9H, m), 1.11 (3H, d, J = 6.0Hz)

[1903] 质量(m/e)550(M+1) [1903] mass (m / e) 550 (M + 1)

[1904] 实施例106:合成1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基吡咯烷-2-酮 [1904] Example 106: Synthesis of 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-pyrrolidin-2-one

[1905] [1905]

[1906] 除了利用制备178获得的26.0mg(0.0471mmol){(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代吡咯烷-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得12.5mg标题化合物,收率54%。 [1906] In addition to 26.0mg (0.0471mmol) {(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydropyridine is obtained and prepared using 178 [ 3,4-d] pyrimidin -7 (6H) - yl] -1 - [(4-methyl-2-oxo-pyrrolidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - addition butyl ester, in the same manner as in Example 22 to obtain 12.5mg of the title compound in 54% yield.

[1907] 1H NMR(CD3OD)δ8.36(1H,s),7.65(1H,s),7.09(1H,s),4.91-4.84(2H,m),3.97(1H,brs),3.87(2H,brs),3.71-3.58(3H,m),3.14(2H,brs),3.04-2.99(2H,m),2.86-2.79(1H,m),2.60-2.51(1H,m),2.10-2.05(2H,m),1.22-1.16(3H,m) [1907] 1H NMR (CD3OD) δ8.36 (1H, s), 7.65 (1H, s), 7.09 (1H, s), 4.91-4.84 (2H, m), 3.97 (1H, brs), 3.87 (2H , brs), 3.71-3.58 (3H, m), 3.14 (2H, brs), 3.04-2.99 (2H, m), 2.86-2.79 (1H, m), 2.60-2.51 (1H, m), 2.10-2.05 (2H, m), 1.22-1.16 (3H, m)

[1908] 质量(m/e)450(M+1) [1908] mass (m / e) 450 (M + 1)

[1909] 制备179:合成[(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代-1-{[2-氧代-5-(三氟甲基)哌啶-1-基]甲基}丙基]氨基甲酸叔-丁酯 [1909] Preparation 179: Synthesis of [(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -3-oxo-1 - {[2-oxo-5- (trifluoromethyl) piperidin-1-yl] methyl} propyl] carbamic acid tert - butyl ester

[1910] 除了利用制备170的14.0mg(0.038mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-5-(三氟甲基)哌啶-1-基]丁酸和制备127获得的12.3mg(0.038mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得18.0mg标题化合物,收率76%。 [1910] In addition to 170 prepared using 14.0mg (0.038mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidine 1-yl] butanoic acid was prepared and 127 12.3mg (0.038mmol) 2,4- bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine obtained other than hydrochloride in the same manner as in preparation 45 to give the title compound 18.0mg, yield 76%.

[1911] 1H NMR(CDCl3)δ5.86-5.76(1H,m),5.04-4.91(2H,m),4.17(1H,brs),4.15-3.78(2H,m),3.68-3.44(4H,m),3.22-3.10(2H,m),2.87-2.80(1H,m),2.60-2.45(3H,m),2.36-2.30(1H,m),2.07(1H,brs),1.88-1.84(1H,m),1.40-1.39(9H,m) [1911] 1H NMR (CDCl3) δ5.86-5.76 (1H, m), 5.04-4.91 (2H, m), 4.17 (1H, brs), 4.15-3.78 (2H, m), 3.68-3.44 (4H, m), 3.22-3.10 (2H, m), 2.87-2.80 (1H, m), 2.60-2.45 (3H, m), 2.36-2.30 (1H, m), 2.07 (1H, brs), 1.88-1.84 ( 1H, m), 1.40-1.39 (9H, m)

[1912] 质量(m/e)622(M+1) [1912] mass (m / e) 622 (M + 1)

[1913] 实施例107:合成1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-(三氟甲基)哌啶-2-酮 [1913] Example 107: Synthesis of 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -5- (trifluoromethyl) piperidin-2-one

[1914] [1914]

[1915] 除了利用制备178获得的18.0mg(0.0289mmol)[(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代-1-{[2-氧代-5-(三氟甲基)哌啶-1-基]甲基}丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得13.3mg标题化合物,收率83%。 [1915] Preparation 178 except for using the obtained 18.0mg (0.0289mmol) [(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxo-1 - {[2-oxo-5- (trifluoromethyl) piperidin-1-yl] methyl} propyl] carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to give the title compound 13.3mg, 83% yield.

[1916] 1H NMR(CD3OD)δ4.94-4.79(2H,m),3.89-3.86(1H,m),3.82-3.72(2H,m),3.66-3.52(5H,m),3.16-3.11(1H,m),3.04(1H,brs),2.94-2.73(2H,m),2.43-2.41(2H,m),2.08-2.02(1H,m),1.89-1.82(1H,m) [1916] 1H NMR (CD3OD) δ4.94-4.79 (2H, m), 3.89-3.86 (1H, m), 3.82-3.72 (2H, m), 3.66-3.52 (5H, m), 3.16-3.11 ( 1H, m), 3.04 (1H, brs), 2.94-2.73 (2H, m), 2.43-2.41 (2H, m), 2.08-2.02 (1H, m), 1.89-1.82 (1H, m)

[1917] 质量(m/e)522(M+1) [1917] mass (m / e) 522 (M + 1)

[1918] 制备180:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代-1-{[2-氧代-4-(三氟甲基)吡咯烷-1-基]甲基}丙基}氨基甲酸叔-丁酯 [1918] Preparation 180: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -3-oxo-1 - {[2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] methyl} propyl} carbamic acid tert - butyl ester

[1919] 除了利用制备172获得的25.0mg(0.061mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-4-(三氟甲基)吡咯烷-1-基]丁酸和制备127获得的31.5mg(0.061mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得21.0mg标题化合物,收率41%。 [1919] In addition to 172 prepared using the obtained 25.0mg (0.061mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrole 1-yl] butyric acid and 127 obtained in preparation 31.5mg (0.061 mmol) 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give the title compound 21.0mg, yield 41%.

[1920] 1H NMR(CDCl3)δ5.59(1H,brs),5.04-4.80(2H,m),4.17-4.11(1H,m),4.02-3.82(2H,m),3.75-3.66(2H,m),3.63-3.58(2H,m),3.20-3.04(3H,m),2.86-2.75(1H,m),2.64-2.39(3H,m),1.42-1.40(9H,m) [1920] 1H NMR (CDCl3) δ5.59 (1H, brs), 5.04-4.80 (2H, m), 4.17-4.11 (1H, m), 4.02-3.82 (2H, m), 3.75-3.66 (2H, m), 3.63-3.58 (2H, m), 3.20-3.04 (3H, m), 2.86-2.75 (1H, m), 2.64-2.39 (3H, m), 1.42-1.40 (9H, m)

[1921] 质量(m/e)608(M+1) [1921] mass (m / e) 608 (M + 1)

[1922] 实施例108:合成1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-(三氟甲基)吡咯烷-2-酮 [1922] Example 108: Synthesis of 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one

[1923] [1923]

[1924] 除了利用制备180获得的21.0mg(0.0346mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代-1-{[2-氧代-4-(三氟甲基)吡咯烷-1-基]甲基}丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得18.2mg标题化合物,收率96%。 [1924] In addition to 180 prepared using the obtained 21.0mg (0.0346mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -3-oxo-1 - {[2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] methyl} propyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to give the title compound 18.2mg, yield 96%.

[1925] 1H NMR(CD3OD)δ5.01-4.91(2H,m),3.98-3.76(4H,m),3.72-3.52(4H,m),3.22(1H,brs),3.11(1H,m),3.03-2.94(1H,m),2.89-2.80(1H,m),2.73-2.65(1H,m),2.57-2.52(1H,m) [1925] 1H NMR (CD3OD) δ5.01-4.91 (2H, m), 3.98-3.76 (4H, m), 3.72-3.52 (4H, m), 3.22 (1H, brs), 3.11 (1H, m) , 3.03-2.94 (1H, m), 2.89-2.80 (1H, m), 2.73-2.65 (1H, m), 2.57-2.52 (1H, m)

[1926] 质量(m/e)508(M+1) [1926] mass (m / e) 508 (M + 1)

[1927] 制备181:合成[(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代-1-{[2-氧代-4-(三氟甲基)吡咯烷-1-基]甲基}丙基]氨基甲酸叔-丁酯 [1927] Preparation 181: Synthesis of [(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -3-oxo-1 - {[2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] methyl} propyl] carbamic acid tert - butyl ester

[1928] 除了利用制备172获得的25.0mg(0.061mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[2-氧代-4-(三氟甲基)吡咯烷-1-基]丁酸和制备96获得的22.0mg(0.061mmol)2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得30.0mg标题化合物,收率82%。 [1928] In addition to 172 prepared using the obtained 25.0mg (0.061mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrole 1-yl] butyric acid and 22.0 mg (0.061 mmol) obtained in preparation 96 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [ other than 3,4-d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give 30.0mg of the title compound in 82% yield.

[1929] 1H NMR(CDCl3)δ8.26(1H,s),7.49(1H,d,J=1.2Hz),7.04(1H,d,J=6.1Hz),5.61-5.55(1H,m),4.84(2H,s),4.76-4.68(2H,m),4.18(1H,brs),3.98(1H,brs),3.74-3.46(4H,m),3.10-2.98(3H,m),2.83-2.77(1H,m),2.63-2.50(3H,m),1.41-1.39(9H,m) [1929] 1H NMR (CDCl3) δ8.26 (1H, s), 7.49 (1H, d, J = 1.2Hz), 7.04 (1H, d, J = 6.1Hz), 5.61-5.55 (1H, m), 4.84 (2H, s), 4.76-4.68 (2H, m), 4.18 (1H, brs), 3.98 (1H, brs), 3.74-3.46 (4H, m), 3.10-2.98 (3H, m), 2.83- 2.77 (1H, m), 2.63-2.50 (3H, m), 1.41-1.39 (9H, m)

[1930] 质量(m/e)606(M+1) [1930] mass (m / e) 606 (M + 1)

[1931] 实施例109:合成1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-(三氟甲基)吡咯烷-2-酮 [1931] Example 109: Synthesis of 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one

[1932] [1932]

[1933] 除了利用制备181获得的30.0mg(0.050mmol)[(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-3-氧代-1-{[2-氧代-4-(三氟甲基)吡咯烷-1-基]甲基}丙基]氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得24.7mg标题化合物,收率92%。 [1933] In addition to 181 prepared using the obtained 30.0mg (0.050mmol) [(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -3-oxo-1 - {[2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] methyl} propyl ] carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 24.7mg of the title compound in 92% yield.

[1934] 1H NMR(CD3OD)δ8.36(1H,s),7.65(1H,s),7.09(1H,s),4.92-4.90(2H,m),3.97-3.80(4H,m),3.70-3.55(4H,m),3.15-3.10(1H,m),3.05-3.95(2H,m),2.85-2.72(2H,m),2.65-2.55(1H,m) [1934] 1H NMR (CD3OD) δ8.36 (1H, s), 7.65 (1H, s), 7.09 (1H, s), 4.92-4.90 (2H, m), 3.97-3.80 (4H, m), 3.70 -3.55 (4H, m), 3.15-3.10 (1H, m), 3.05-3.95 (2H, m), 2.85-2.72 (2H, m), 2.65-2.55 (1H, m)

[1935] 质量(m/e)506(M+1) [1935] mass (m / e) 506 (M + 1)

[1936] 制备182:合成{(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1936] Preparation 182: Synthesis of {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl ] -1 - [(4-methyl-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1937] 除了利用制备174获得的30.0mg(0.096mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代哌啶-1-基)丁酸和制备127获得的29.4mg(0.096mmol)2,4-双(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得25mg标题化合物,收率46%。 [1937] Preparation 174 except for using the obtained 30.0mg (0.096mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-piperidine-1 29.4mg-yl) butyric acid and obtained in preparation 127 (0.096 mmol) 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride addition, in the same manner as in preparation 45 to give the title compound 25mg, 46% yield.

[1938] 1H NMR(CDCl3)δ6.00-5.94(1H,m),5.12-4.81(2H,m),4.19-4.05(2H,m),3.88(2H,brs),3.74-3.66(1H,m),3.50-3.40(3H,m),3.30-3.15(2H,m),2.93-2.82(1H,m),2.58-2.37(2H,m),2.00-1.88(3H,m),1.46-1.44(9H,m),1.04-1.03(3H,m) [1938] 1H NMR (CDCl3) δ6.00-5.94 (1H, m), 5.12-4.81 (2H, m), 4.19-4.05 (2H, m), 3.88 (2H, brs), 3.74-3.66 (1H, m), 3.50-3.40 (3H, m), 3.30-3.15 (2H, m), 2.93-2.82 (1H, m), 2.58-2.37 (2H, m), 2.00-1.88 (3H, m), 1.46- 1.44 (9H, m), 1.04-1.03 (3H, m)

[1939] 质量(m/e)568(M+1) [1939] mass (m / e) 568 (M + 1)

[1940] 实施例110:合成1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基氧代哌啶-2-酮 [1940] Example 110: Synthesis of 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -4-methyl-2-oxopiperidine

[1941] [1941]

[1942] 除了利用制备182获得的25mg(0.044mmol){(1S)-3-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得21mg标题化合物,收率95%。 [1942] In addition to 182 prepared using the obtained 25mg (0.044mmol) {(1S) -3- [2,4- bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -1 - [(4-methyl-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester addition to the same manner as Example 22 to obtain 21mg of the title compound in 95% yield.

[1943] 1H NMR(CD3OD)δ5.06-4.94(2H,m),4.00-3.86(3H,m),3.82-3.74(1H,m),3.61-3.59(1H,m),3.50-3.45(2H,m),3.26(1H,brs),3.15(1H,brs),3.05-2.98(1H,m),2.92-2.85(1H,m),2.47-2.44(1H,m),2.07-1.92(3H,m),1.57(1H,brs),1.05(3H,d,J=4.8Hz) [1943] 1H NMR (CD3OD) δ5.06-4.94 (2H, m), 4.00-3.86 (3H, m), 3.82-3.74 (1H, m), 3.61-3.59 (1H, m), 3.50-3.45 ( 2H, m), 3.26 (1H, brs), 3.15 (1H, brs), 3.05-2.98 (1H, m), 2.92-2.85 (1H, m), 2.47-2.44 (1H, m), 2.07-1.92 ( 3H, m), 1.57 (1H, brs), 1.05 (3H, d, J = 4.8Hz)

[1944] 质量(m/e)468(M+1) [1944] mass (m / e) 468 (M + 1)

[1945] 制备183:合成{(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1945] Preparation 183: Synthesis of {(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -1 - [(4-methyl-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1946] 除了利用制备174获得的30.0mg(0.096mmol)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(4-甲基-2-氧代吡咯烷-1-基)丁酸和制备96获得的29.2mg(0.096mmol)2-(3-呋喃基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得43mg标题化合物,收率80%。 [1946] Preparation 174 except for using the obtained 30.0mg (0.096mmol) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (4-methyl-2-oxo-pyrrolidin-1 yl) butyric acid and 96 obtained in preparation 29.2mg (0.096mmol) 2- (3- furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition d] pyrimidine hydrochloride, in the same manner as in preparation 45, to obtain 43mg of the title compound in 80% yield.

[1947] 1H NMR(CDCl3)δ8.30(1H,s),7.54-7.53(1H,m),7.09(1H,s),5.92-5.90(1H,m),4.89(1H,s),4.80-4.76(1H,m),4.23(1H,brs),3.94-3.79(3H,m),3.68-3.39(4H,m),3.11-3.03(2H,m),2.97-2.87(1H,m),2.57-2.47(2H,m),2.03-1.87(3H,m),1.46-1.44(9H,m),1.03(3H,d,J=5.6Hz) [1947] 1H NMR (CDCl3) δ8.30 (1H, s), 7.54-7.53 (1H, m), 7.09 (1H, s), 5.92-5.90 (1H, m), 4.89 (1H, s), 4.80 -4.76 (1H, m), 4.23 (1H, brs), 3.94-3.79 (3H, m), 3.68-3.39 (4H, m), 3.11-3.03 (2H, m), 2.97-2.87 (1H, m) , 2.57-2.47 (2H, m), 2.03-1.87 (3H, m), 1.46-1.44 (9H, m), 1.03 (3H, d, J = 5.6Hz)

[1948] 质量(m/e)566(M+1) [1948] mass (m / e) 566 (M + 1)

[1949] 实施例111:合成1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基哌啶-2-酮 [1949] Example 111: Synthesis of 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-piperidin-2-one

[1950] [1950]

[1951] 除了利用制备183获得的43mg(0.076mmol){(1S)-3-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(4-甲基-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得37mg标题化合物,收率97%。 [1951] In addition to 183 prepared using the obtained 43mg (0.076mmol) {(1S) -3- [2- (3- furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -1 - [(4-methyl-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl outside, in the same manner as in Example 22 to obtain 37mg of the title compound in 97% yield.

[1952] 1H NMR(CD3OD)δ8.24(1H,d,J=0.8Hz),7.57-7.52(1H,m),6.96(1H,d,J=1.2Hz),4.79-4.73(2H,m),3.90-3.82(4H,m),3.77-3.71(1H,m),3.51-3.47(1H,m),3.43-3.31(2H,m),3.03(1H,brs),2.97-2.90(1H,m),2.84-2.75(1H,m),2.40-2.34(1H,m),2.01-1.80(3H,m),1.46(1H,brs),0.93(3H,d,J=4.0Hz) [1952] 1H NMR (CD3OD) δ8.24 (1H, d, J = 0.8Hz), 7.57-7.52 (1H, m), 6.96 (1H, d, J = 1.2Hz), 4.79-4.73 (2H, m ), 3.90-3.82 (4H, m), 3.77-3.71 (1H, m), 3.51-3.47 (1H, m), 3.43-3.31 (2H, m), 3.03 (1H, brs), 2.97-2.90 (1H , m), 2.84-2.75 (1H, m), 2.40-2.34 (1H, m), 2.01-1.80 (3H, m), 1.46 (1H, brs), 0.93 (3H, d, J = 4.0Hz)

[1953] 质量(m/e)466(M+1) [1953] mass (m / e) 466 (M + 1)

[1954] 制备184:合成2-环丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1954] Preparation 184: Synthesis of 2-cyclobutyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1955] (1)合成环丁烷羧酰亚胺酰胺(carboxymidamide) [1955] (1) Synthesis of cyclobutane carboxylic acid amide imide (carboxymidamide)

[1956] 除了利用1.22g(15mmol)环丁烷甲腈之外,以制备58-(1)的相同方式,获得1.28g标题化合物,收率87%。 [1956] In addition cyclobutanecarbonitrile using 1.22g (15mmol) outside, in the same manner as the preparation of 58- (1), to obtain 1.28g of the title compound in 87% yield.

[1957] NMR:1H-NMR(CD3OD)δ3.50(1H,m),2.35(4H,m),2.1(1H,m),1.9(1H,m) [1957] NMR: 1H-NMR (CD3OD) δ3.50 (1H, m), 2.35 (4H, m), 2.1 (1H, m), 1.9 (1H, m)

[1958] (2)合成叔-丁基-2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯 [1958] (2) Synthesis of tert - butyl-2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - carboxamide ester

[1959] 除了利用500mg(1.69mmol)3-氧代-4-(三氟乙酰)哌啶-1-羧酸叔-丁酯和上述步骤(1)获得的166mg(1.69mmol)环丁烷羧酰亚胺酰胺之外,以制备58-(2)的相同方式,获得200mg标题化合物,收率33%。 [1959] Besides using 500mg (1.69mmol) 3- oxo-4- (trifluoroacetyl) piperidine-1-carboxylic acid tert - 166mg ester and the above-described step (1) obtained in (1.69 mmol) cyclobutanecarboxamide addition polyimide amide, was prepared in the same manner as 58- (2), to obtain 200mg of the title compound in 33% yield.

[1960] 1H NMR(CDCl3)δ4.69(2H,s),3.80(1H,m),3.70(2H,t,J=5.5Hz),2.97(2H,br s),2.45(2H,m),2.37(2H,m),2.08(1H,m),1.96(1H,m),1.49(9H,s) [1960] 1H NMR (CDCl3) δ4.69 (2H, s), 3.80 (1H, m), 3.70 (2H, t, J = 5.5Hz), 2.97 (2H, br s), 2.45 (2H, m) , 2.37 (2H, m), 2.08 (1H, m), 1.96 (1H, m), 1.49 (9H, s)

[1961] 质量(m/e)358(M+1) [1961] mass (m / e) 358 (M + 1)

[1962] (3)合成2-环丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐 [1962] (3) Synthesis of 2-cyclobutyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine hydrochloride

[1963] 除了利用上述步骤(2)获得的200mg(0.56mmol)叔-丁基-2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸酯之外,以制备58-(3)的相同方式,获得100mg标题化合物,收率69%。 [1963] 200mg except for using the above-described step (2) obtained in (0.56 mmol) tert - butyl-2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - outside carboxylate, was prepared in the same manner as 58- (3), to obtain 100mg of the title compound in 69% yield.

[1964] 1H NMR(CD3OD)δ4.47(2H,s),3.85(1H,m),3.59(2H,t,J=6.5Hz),3.29(2H,br s),2.4(4H,m),2.14(1H,m),1.95(1H,m) [1964] 1H NMR (CD3OD) δ4.47 (2H, s), 3.85 (1H, m), 3.59 (2H, t, J = 6.5Hz), 3.29 (2H, br s), 2.4 (4H, m) , 2.14 (1H, m), 1.95 (1H, m)

[1965] 质量(m/e)258(M+1) [1965] mass (m / e) 258 (M + 1)

[1966] 制备185:合成{(1S)-3-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基}氨基甲酸叔-丁酯 [1966] Preparation 185: Synthesis of {(1S) -3- [2- cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} carbamic acid tert - butyl ester

[1967] 除了利用制备51获得的57mg(0.181mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-[(5R)-5-甲基-2-氧代哌啶-1-基]丁酸和制备184获得的40.0mg(0.164mmole)2-环丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得65.0mg标题化合物,收率65%。 [1967] Preparation 51 except for using the obtained 57mg (0.181mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4 - [(5R) -5- methyl-2-oxopiperidine 1-yl] butyric acid and 184 obtained in preparation 40.0mg (0.164mmole) 2- cyclobutyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4- addition d] pyrimidine hydrochloride, in the same manner as in preparation 45 to give the title compound 65.0mg, yield 65%.

[1968] 1H NMR(CDCl3)δ5.87-5.83(1H,m),4.88-4.80(1H,m),4.75-4.64(1H,m),4.18-4.15(1H,m),3.90-3.74(3H,m),3.58-3.47(2H,m),3.36-3.33(1H,m),3.08-2.96(3H,m),2.86-2.80(1H,m),2.50-2.30(8H,m),2.10-2.03(1H,m),2.00-1.90(2H,m),1.81-1.78(1H,m),1.43-1.39(9H,m),0.99-0.98(3H,m) [1968] 1H NMR (CDCl3) δ5.87-5.83 (1H, m), 4.88-4.80 (1H, m), 4.75-4.64 (1H, m), 4.18-4.15 (1H, m), 3.90-3.74 ( 3H, m), 3.58-3.47 (2H, m), 3.36-3.33 (1H, m), 3.08-2.96 (3H, m), 2.86-2.80 (1H, m), 2.50-2.30 (8H, m), 2.10-2.03 (1H, m), 2.00-1.90 (2H, m), 1.81-1.78 (1H, m), 1.43-1.39 (9H, m), 0.99-0.98 (3H, m)

[1969] 质量(m/e)554(M+1) [1969] mass (m / e) 554 (M + 1)

[1970] 实施例112:合成(5R)-1-{(2S)-2-氨基-4-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮 [1970] Example 112: Synthesis of (5R) -1 - {(2S) -2- amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one

[1971] [1971]

[1972] 除了利用制备185获得的65.0mg(0.117mmole){(1S)-3-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-{[(5R)-5-甲基-2-氧代哌啶-1-基]甲基}-3-氧代丙基1}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得42.4mg标题化合物,收率80%。 [1972] Besides using 65.0mg (0.117mmole) {(1S) -3- [2- cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyridine obtained in Preparation 185 [3,4 -d] pyrimidin -7 (6H) - yl] -1 - {[(5R) -5- methyl-2-oxo-piperidin-1-yl] methyl} -3-oxopropyl} amino-1 acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 42.4mg of the title compound in 80% yield.

[1973] 1H NMR(CD3OD)δ4.92-4.80(2H,m),3.91-3.83(3H,m),3.64-3.62(1H,m),3.55-3.41(3H,m),3.11-3.00(3H,m),2.78-2.73(1H,m),2.65-2.56(1H,m),2.52-2.31(6H,m),2.19-2.100(1H,m),2.03-1.94(2H,m),1.87-1.84(1H,m),1.58-1.47(1H,m),1.04(3H,d,J=6.8Hz) [1973] 1H NMR (CD3OD) δ4.92-4.80 (2H, m), 3.91-3.83 (3H, m), 3.64-3.62 (1H, m), 3.55-3.41 (3H, m), 3.11-3.00 ( 3H, m), 2.78-2.73 (1H, m), 2.65-2.56 (1H, m), 2.52-2.31 (6H, m), 2.19-2.100 (1H, m), 2.03-1.94 (2H, m), 1.87-1.84 (1H, m), 1.58-1.47 (1H, m), 1.04 (3H, d, J = 6.8Hz)

[1974] 质量(m/e)454(M+1) [1974] mass (m / e) 454 (M + 1)

[1975] 制备186:合成{(1S)-3-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯 [1975] Preparation 186: Synthesis of {(1S) -3- [2- cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester

[1976] 除了利用制备57的61mg(0.181mmole)(3S)-3-[(叔-丁氧基羰基)氨基]-4-(5,5-二氟-2-氧代哌啶-1-基)丁酸和制备194获得的40.0mg(0.164mmole)2-环丁基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐之外,以制备45的相同方式,获得67.0mg标题化合物,收率64%。 [1976] In addition to using 61mg 57 Preparation of (0.181mmole) (3S) -3 - [(tert - butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxo-piperidine-1 yl) butyric acid and 40.0mg (0.164mmole) 194 preparation of 2- cyclobutyl-4- (trifluoromethyl) -5,6,7,8-tetrahydro-pyrido [3,4-d] pyrimidine other than hydrochloride in the same manner as in preparation 45 to give the title compound 67.0mg, yield 64%.

[1977] 1H NMR(CDCl3)δ5.77(1H,brs),4.88-4.80(1H,m),4.73-4.65(1H,m),4.22-4.18(1H,m),3.88-3.68(5H,m),3.59-3.48(2H,m),3.04-2.98(2H,m),2.84-2.79(1H,m),2.58-2.50(3H,m),2.48-2.34(4H,m),2.30-2.20(2H,m),2.10-2.03(1H,m),1.98-1.92(1H,m),1.41-1.40(9H,m) [1977] 1H NMR (CDCl3) δ5.77 (1H, brs), 4.88-4.80 (1H, m), 4.73-4.65 (1H, m), 4.22-4.18 (1H, m), 3.88-3.68 (5H, m), 3.59-3.48 (2H, m), 3.04-2.98 (2H, m), 2.84-2.79 (1H, m), 2.58-2.50 (3H, m), 2.48-2.34 (4H, m), 2.30- 2.20 (2H, m), 2.10-2.03 (1H, m), 1.98-1.92 (1H, m), 1.41-1.40 (9H, m)

[1978] 质量(m/e)576(M+1-Boc) [1978] mass (m / e) 576 (M + 1-Boc)

[1979] 实施例113:合成1-{(2S)-2-氨基-4-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮 [1979] Example 113: Synthesis of 1 - {(2S) -2- amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

[1980] [1980]

[1981] 除了利用制备186获得的67mg(0.116mmole){(1S)-3-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-1-[(5,5-二氟-2-氧代哌啶-1-基)甲基]-3-氧代丙基}氨基甲酸叔-丁酯之外,以实施例22的相同方式,获得43.9mg标题化合物,收率79%。 [1981] A prepared using 186 67mg (0.116mmole) {(1S) -3- [2- cyclobutyl-4- (trifluoromethyl) pyridine and 5,8-dihydro [3,4 d] pyrimidin -7 (6H) - yl] -1 - [(5,5-difluoro-2-oxo-piperidin-1-yl) methyl] -3-oxopropyl} carbamic acid tert - butyl ester addition, in the same manner as in Example 22 to obtain 43.9mg of the title compound in 79% yield.

[1982] 1H NMR(CD3OD)δ4.91-4.79(2H,m),3.87-3.80(5H,m),3.53-3.48(3H,m),3.10-3.00(2H,m),2.73-2.32(9H,m),2.14-2.11(1H,m),1.99-1.96(2H,m) [1982] 1H NMR (CD3OD) δ4.91-4.79 (2H, m), 3.87-3.80 (5H, m), 3.53-3.48 (3H, m), 3.10-3.00 (2H, m), 2.73-2.32 ( 9H, m), 2.14-2.11 (1H, m), 1.99-1.96 (2H, m)

[1983] 质量(m/e)476(M+1) [1983] mass (m / e) 476 (M + 1)

[1984] 实验:DPP-IV活性-抑制能力的测量 [1984] Experiment: DPP-IV activity - measurement of ability to inhibit

[1985] 二肽基肽酶-IV(DPP-IV),已知是丝氨酸蛋白酶,其通过公知方法修饰而获得(Tanaka T.等,Proc.Natl.Acad.Sci.USA,(1994)91,3082-3086),该方法包括克隆、利用杆状病毒纯化、以及活化步骤。 [1985] Dipeptidyl peptidase -IV (DPP-IV), known to be a serine protease, is obtained (Tanaka T. et, Proc which modified by known methods, (1994) 91, 3082-3086), which comprises cloning, purification using baculovirus, as well as the activation step. 如下文所述,DPP-IV用于测试候选抑制剂的药物功效。 As described below, DPP-IV inhibitors for the candidate drug efficacy testing. 克隆的DP-IV在杆状病毒中表达,经过镍柱纯化,再进行透析。 The cloned DP-IV expression in baculovirus, through a nickel column purification, followed by dialysis. 利用荧光底物Ac-Gly-Pro-AFC,测试实施例合成的抑制剂,确定其结合活性。 Using the fluorogenic substrate Ac-Gly-Pro-AFC, Synthesis Example of the test inhibitor, which determine the binding activity. 利用100μM Ac-Gly-Pro-AFC,25℃下,在含有50mmol HEPES(pH 7.4)的缓冲液中,DP-IV浓度为7.1nM,对多种浓度的抑制剂进行酶反应。 Using 100μM Ac-Gly-Pro-AFC, at 25 ℃, in buffer containing 50mmol HEPES (pH 7.4) in, DP-IV at a concentration of 7.1nM, various concentrations of inhibitor to enzyme reaction. 抑制剂的IC50值的确定方法为,在酶反应1小时之后,测量荧光分光计发射的荧光量,然后计算抑制全部酶反应50%的抑制剂浓度。 The method of determination of IC50 values ​​of inhibitors, one hour after the enzymatic reaction, measuring the amount of fluorescence emitted fluorescence spectrometer, and all of the enzyme reaction inhibition was calculated inhibitor concentration of 50%. Molecular Device Co.的Spectra MAX GeminiXS荧光分光计用作荧光分光计,而激发频率和发射频率分别设定在400nm和505nm。 Molecular Device Co.'s Spectra MAX GeminiXS fluorescent spectrometer as fluorescence spectrometer, and the excitation frequency and emission frequency were set at 400nm and 505nm. 结果总结在下表1中。 The results are summarized in Table 1 below.

[1986] [表1] [1986] [Table 1]

[1987] [1987]

[1988] [1988]

[1989] [1989]

[1990] 工业实用性 [1990] Industrial Applicability

[1991] 如上所述,本发明的新型化合物抑制DPP-IV活性,导致高胰岛素水平以及低血糖水平。 [1991] As described above, the novel compounds of the present invention to inhibit DPP-IV activity, resulting in high insulin levels and low blood sugar levels. 因此,这些化合物可用作制剂,治疗或预防DPP-IV相关疾病,例如,糖尿病(尤其是II型),肥胖等。 Thus, these compounds are useful as agents for treating or preventing DPP-IV related diseases, e.g., diabetes (especially type II), obesity and the like.

[1992] 本发明的其他实施方案和应用对本领域技术人员而言,从在此公开的说明书和本发明的实践中将是显而易见的。 [1992] Other embodiments and applications of the present invention to those skilled in the art from the specification and in the practice of the invention disclosed herein will be apparent. 说明书和实施例仅视为举例,本发明具体实施方案的范围由权利要求指示。 Specification and examples be considered as way of example only, the scope of the specific embodiments of the invention indicated by the following claims.

Claims (10)

1.下式(1)的化合物或其可药用盐: 1. The compound of formula (1) or a pharmaceutically acceptable salt thereof:
其中 among them
(A)A选自下式(2)-(7)的取代基: (A) A is selected from the following formulas (2) - (7) substituents:
其中R1是氢,或取代或未取代的C1-C4烷基;以及X是碳或氮; Wherein R1 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl; and X is carbon or nitrogen;
其中R2是氢,或取代或未取代的C1-C4烷基; Wherein R2 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl;
其中R3是氢,或取代或未取代的C1-C4烷基,环烷基,芳基或杂芳基;以及R'3是氢,或CF3; Wherein R3 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl, cycloalkyl, aryl or heteroaryl; and R'3 is hydrogen, or CF3;
其中R4是氢,卤素,或取代或未取代的C1-C4烷基,或选自下式(6a)和(6b)的取代基: Wherein R4 is hydrogen, halo, and the substituent (6b) or a substituted or unsubstituted C1-C4 alkyl, or selected from the formula (6a):
其中R5是氢,卤素,或取代或未取代的C1-C4烷基;以及X是氧,硫,或砜; Wherein R5 is hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and X is oxygen, sulfur, or sulfone;
其中R6是卤素,或取代或未取代的C1-C4烷基; Wherein R6 is halogen, or a substituted or unsubstituted C1-C4 alkyl;
(B)B选自下式(8)-(11)的取代基: (B) B is selected from the following formulas (8) - (11) a substituent:
其中R7,R8,R9和R10各自独立为氢,卤素,或取代或未取代的C1-C4烷基; Wherein R7, R8, R9 and R10 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl;
其中R11,R12和R13各自独立为氢,卤素,或取代或未取代的C1-C4烷基;以及Y是氧,硫或SO2; Wherein R11, R12 and R13 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and Y is oxygen, sulfur or of SO2;
其中R14和R15各自独立为氢,卤素,或取代或未取代的C1-C4烷基;以及Z是-CH-或氧,当Z是氧时,没有R14; Wherein R14 and R15 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and Z is -CH- or oxygen, where Z is oxygen, R14 is not;
其中R17是取代或未取代的C1-C4烷基。 Wherein R17 is a substituted or unsubstituted C1-C4 alkyl.
2.权利要求1的化合物或其可药用盐,其中取代的C1-C4烷基是用卤素取代的烷基。 The compound of claim 1 a pharmaceutically acceptable salt thereof, wherein the substituted alkyl group is a C1-C4 alkyl substituted with halogen.
3.权利要求2的化合物或其可药用盐,其中卤素是氟。 3. A compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.
4.权利要求1的化合物或其可药用盐,其中A是式(5)的取代基,以及R3选自下列取代基: 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a substituent of formula (5), and R3 is selected from the following substituents:
氢; hydrogen;
取代或未取代的C1-C4烷基; A substituted or unsubstituted C1-C4 alkyl;
式-CH2-R18,其中R18是C1-C4烷氧基烷基,或未取代或用卤素或羟基取代的C3-C7环烷基,或未取代或用卤素或羟基取代的苯基,或杂芳基; Of formula -CH2-R18, wherein R18 is C1-C4 alkoxy group, or an unsubstituted or substituted by halogen or hydroxy a C3-C7 cycloalkyl, or an unsubstituted or substituted by halogen, hydroxyl or phenyl, heteroaryl, or Aryl;
取代或未取代的C3-C7环烷基; A substituted or unsubstituted C3-C7 cycloalkyl group;
formula
其中R19和R20各自独立为氢,卤素,或取代或未取代的C1-C4烷基;和 Wherein R19 and R20 are each independently hydrogen, halo, a substituted or unsubstituted C1-C4 alkyl; and
未取代或用卤素或羟基取代的5元或6元杂芳基。 Unsubstituted or substituted with halogen or hydroxy-substituted 5-membered or 6-membered heteroaryl.
5.权利要求4的化合物或其可药用盐,其中取代的C3-C7环烷基和C1-C4烷基是用卤素或羟基取代的环烷基和烷基。 Compound 4 may be a pharmaceutically acceptable salt thereof according to claim 1, wherein the substituted C3-C7 cycloalkyl and C1-C4 alkyl substituted with halogen or hydroxy and alkyl cycloalkyl.
6.权利要求1的化合物或其可药用盐,其中杂芳基是2-呋喃,3-呋喃,2-噻吩,3-噻吩,2-吡啶,3-吡啶,4-吡啶,2-吡咯或3-吡咯。 The compound 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl claim or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, or 3-pyrrolyl.
7.权利要求1的化合物或其可药用盐,其中所述化合物是下式(1a)所示的立体异构体: Compound 1 may be a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is a stereoisomer of formula (1a) shown below:
其中A和B与式(1)的相同。 Wherein A and B are the same as in the formula (1).
8.权利要求1的化合物或其可药用盐,其中所述化合物选自下列化合物: The compound of claim 1 a pharmaceutically acceptable salt thereof, wherein said compound is selected from the following:
3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-噁唑烷-2-酮; 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] - oxazolidin-2-one;
3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5-甲基-噁唑烷-2-酮; 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -5-methyl - oxazolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-吡咯烷-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -4-methyl - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4,4-二甲基-吡咯烷-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -4,4-dimethyl - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氟-吡咯烷-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -3-fluoro - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-吡咯烷-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氟-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -3-fluoro - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-甲基-吡咯烷-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -3-methyl - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-1,5-二氢-吡咯-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -4-methyl-1,5-dihydro - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-甲基-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -4-methyl - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5,5-二氟-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -5,5-difluoro - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5R-甲基-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] 5R-methyl - piperidin-2-one;
3-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-3-氮杂-双环[3.1.0]己烷-2-酮; 3- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -3-aza - bicyclo [3.1.0] hexane-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-三氟甲基-吡咯烷-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -4-trifluoromethyl - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-4-三氟甲基-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -4-trifluoromethyl - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-5-三氟甲基-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -5-trifluoromethyl - piperidin-2-one;
4-[2S-氨基-4-氧代-4-(3-三氟甲基-5,6-二氢-8H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-丁基]-6-甲基-吗啉-3-酮; 4- [2S- amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro -8H- [1,2,4] triazolo [4,3-a] pyrazine 7-yl) - butyl] -6-methyl - morpholin-3-one;
1-[2S-氨基-4-(3,4-二氢-1H-异喹啉-2-基)-4-氧代-丁基]-哌啶-2-酮; 1- [2S- Amino-4- (3,4-dihydro -1H- isoquinolin-2-yl) -4-oxo - butyl] - piperidin-2-one;
1-[2S-氨基-4-(3,4-二氢-1H-异喹啉-2-基)-4-氧代-丁基]-4-甲基-吡咯烷-2-酮; 1- [2S- Amino-4- (3,4-dihydro -1H- isoquinolin-2-yl) -4-oxo - butyl] -4-methyl - pyrrolidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-4,5-二氢-7H-异噁唑并[3,4-c]吡啶-6-基)丁基]-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-4,5-dihydro -7H- isoxazolo [3,4-c] pyridin-6-yl) butyl ] - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(3-三氟甲基-1,4,5,7-四氢-吡唑并[3,4-c]吡啶-6-基)-丁基]-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (3-trifluoromethyl-4,5,7-tetrahydro - pyrazolo [3,4-c] pyridin-6-yl) - butyl] - piperidin-2-one;
1-[2S-氨基-4-氧代-4-(4-三氟甲基-5,8-二氢-6H-吡啶并[3,4-d]嘧啶-7-基)-丁基]-5R-甲基-1-哌啶-2-酮; 1- [2S- amino-4-oxo-4- (4-trifluoromethyl-5,8-dihydro--6H- pyrido [3,4-d] pyrimidin-7-yl) - butyl] -5R- -1-methyl-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] butyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[2-苯基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
1-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
1-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-环丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] butyl} -5 , 5-difluoro-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[5-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydro-isoquinoline -2 (1H) - yl] butanoate yl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-2-酮; (6S) -4 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl morpholin-2-one;
1-{(2S)-2-氨基-4-[2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-(3-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
(5R)-1-{(2S)-2-氨基-4-[2-(4-氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
(5R)-1-{(2S)-2-氨基-4-[2-(3,4-二氟苯基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-[2-环戊基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-5-甲基哌啶-2-酮; (5R) -1 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazole and [4,5, c] pyridin -5 (4H) - yl} butyl] -5-methyl-piperidin-2-one;
(6S)-4-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-6-甲基吗啉-3-酮; (6S) -4 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazole and [4,5, c] pyridin -5 (4H) - yl} butyl] -6-methyl-morpholin-3-one;
1-[(2S)-2-氨基-4-氧代-4-{2-[4-(三氟甲基)苯基]-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基}丁基]-5,5-二氟哌啶-2-酮; 1 - [(2S) -2- amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4, 5, c] pyridin -5 (4H) - yl} butyl] -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(4-氟苯基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine - 5 (4H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(4-氟苯基)6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (4-fluorophenyl) 6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-[2-(4-氟苯基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2R)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2R) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[2-(四氢-2H-吡喃-4-基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2- (tetrahydro -2H- pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4 , 5, c] pyridin -5 (4H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(三氟甲基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin -5 (4H) - yl] butyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[2-(三氟甲基)-6,7-二氢[1,3]噻唑并[4,5,c]吡啶-5(4H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine - 5 (4H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3, 4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(2-甲氧基乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(环丙基甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-4-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(4-氟苄基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-氧代-4-[2-(3-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-氧代-4-[2-(2-噻吩基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(2-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo -4- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro- pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-氧代-4-[2-(1H-吡咯-2-基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo -4- [2- (1H- pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3 , 4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-氧代-4-[2-吡啶-3-基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d ] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
1-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
1-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-异丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
(6R)-4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮; (6R) -4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 , 3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-morpholin-3-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 , 3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-morpholin-3-one;
(5S)-1-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-5-甲基哌啶-2-酮; (5S) -1 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 , 3-a] pyrazin -7 (8H) - yl] butyl} -5-methyl-piperidin-2-one;
(5S)-1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5S) -1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(5R)-4-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (5R) -4 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-甲基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] butyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a ] pyrazine -7 (8H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[3-(五氟乙基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4 , 3-a] pyrazin -7 (8H) - yl] butyl} -6-methyl-morpholin-3-one;
4-{(2S)-2-氨基-4-[2.4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基硫代吗啉-3-酮; 4 - {(2S) -2- amino-4- [2.4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4 - oxobutyl} -6-methyl-thiomorpholine-3-one;
1-{(2S)-2-氨基-4-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H ) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-[2-叔-丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4- [2-tert - butyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine -7 (6H) - yl] -4-oxobutyl} -6-methyl-morpholin-3-one;
4-{(2S)-2-氨基-4-氧代-4-[3-(三氟甲基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]丁基}-6-甲基硫代吗啉-3-酮; 4 - {(2S) -2- amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a ] pyrazine -7 (8H) - yl] butyl} -6-methyl-thiomorpholine-3-one;
(5R)-1-{(2S)-2-氨基-4-[2-乙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
(6S)-4-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-6-甲基吗啉-3-酮; (6S) -4 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [ 3,4-d] pyrimidin -7 (6H) - yl] butyl} -6-methyl-morpholin-3-one;
1-{(2S)-2-氨基-4-氧代-4-[2-(五氟乙基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-氧代-4-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4- d] pyrimidin -7 (6H) - yl] butyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-氧代-4-[2-丙基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] butyl} -5,5-difluoropiperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-(氟甲基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin-7 ( 6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基-1,5-二氢-2H-吡咯-2-酮; 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-1,5-dihydro -2H- pyrrol-2-one;
1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基-1,5-二氢-2H-吡咯-2-酮; 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -4-methyl-1,5-dihydro -2H- pyrrol-2-one;
1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基氧代吡咯烷-2-酮; 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-oxo-2-one;
1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基吡咯烷-2-酮; 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -4-methyl-pyrrolidin-2-one;
1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-(三氟甲基)哌啶-2-酮; 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5- (trifluoromethyl) piperidin-2-one;
1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-(三氟甲基)吡咯烷-2-酮; 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one;
1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-(三氟甲基)吡咯烷-2-酮; 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one;
1-{(2S)-2-氨基-4-[2,4-双(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基氧代哌啶-2-酮; 1 - {(2S) -2- amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -4-methyl-oxo-2-one;
1-{(2S)-2-氨基-4-[2-(3-呋喃基)-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-4-甲基哌啶-2-酮; 1 - {(2S) -2- amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine-7 (6H) - yl] -4-oxobutyl} -4-methyl-piperidin-2-one;
(5R)-1-{(2S)-2-氨基-4-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5-甲基哌啶-2-酮; (5R) -1 - {(2S) -2- amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidine - 7 (6H) - yl] -4-oxobutyl} -5-methyl-piperidin-2-one;
1-{(2S)-2-氨基-4-[2-环丁基-4-(三氟甲基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-基]-4-氧代丁基}-5,5-二氟哌啶-2-酮; 1 - {(2S) -2- amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydro-pyrido [3,4-d] pyrimidin -7 (6H) - yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;
9.一种抑制二肽基肽酶-IV(DPP-IV)的药物组合物,包含权利要求1限定的式1的化合物或其可药用盐以及可药用载体。 9. A method of inhibiting dipeptidyl peptidase -IV (DPP-IV) of the pharmaceutical composition defined in claim 1 comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
10.权利要求9的药物组合物,其中所述组合物用于治疗或预防糖尿病或肥胖。 10. The pharmaceutical composition as claimed in claim 9, wherein the composition is for the treatment or prophylaxis of diabetes or obesity.
CN 200680009935 2005-04-01 2006-03-30 Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent CN101151265B (en)

Priority Applications (9)

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KR20050027756 2005-04-01
KR10-2005-0027756 2005-04-01
KR20050053761 2005-06-22
KR10-2005-0053761 2005-06-22
KR20050085980 2005-09-15
KR10-2005-0085980 2005-09-15
KR10-2005-0122361 2005-12-13
KR20050122361 2005-12-13
PCT/KR2006/001169 WO2006104356A1 (en) 2005-04-01 2006-03-30 Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent

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CN101151265A true CN101151265A (en) 2008-03-26
CN101151265B CN101151265B (